Echoes in the powerhouse: mito-lncRNAs contribution to cardiac function and disease

Abstract

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and its progression is closely linked to mitochondrial dysfunction in cardiomyocytes. Given the high energy demands of the heart, precise regulation of mitochondrial homeostasis, including oxidative phosphorylation, reactive oxygen species balance, calcium handling, and mitophagy, is essential for maintaining cardiac function. Emerging evidence has identified mitochondrial-associated long non-coding RNAs (mito-lncRNAs) as important regulators of these processes. Mito-lncRNAs comprise both nuclear-encoded transcripts that translocate to mitochondria and mitochondrial genome-encoded lncRNAs that function within the organelle. These molecules modulate mitochondrial gene expression, respiratory chain stability, metabolic flux, and stress responses, thereby influencing the pathogenesis of acute myocardial infarction, heart failure, diabetic cardiomyopathy, pulmonary hypertension, and cardiac remodeling. In this review, we categorize mito-lncRNAs based on their genomic origin and mitochondrial localization and summarize their mechanistic roles in cardiovascular physiology and disease. Moreover, the review highlights context-dependent effects of key transcripts such as LIPCAR, MALAT1, RMRP, H19, and lncND5. We further discuss the emerging value of mito-lncRNAs as circulating biomarkers and examine the major challenges that currently limit therapeutic translation, including cardiac- and mitochondrial-specific delivery, mechanistic ambiguity, species conservation, and technical limitations in detection. A deeper understanding of mito-lncRNA biology may provide new insights into mitochondrial regulation in the heart and inform the development of novel diagnostic and therapeutic strategies for CVDs.

Introduction

Cardiovascular diseases (CVDs) are disorders that affect the heart and blood vessels. They are recognized as the foremost cause of mortality and morbidity worldwide, exerting a substantial impact on public health [1–3]. Notably, while mortality from CVDs has decreased in high-income countries (HICs) due to the implementation of evidence-based public health policies and advancements in treatment, low- and middle-income countries (LMICs) continue to experience the majority of CVD-related deaths [1]. CVDs originate from intricate molecular and cellular processes that collectively contribute to the pathogenesis of these conditions [4].

Mitochondria contribute to the pathology of CVDs through several interconnected mechanisms, including the disruption of energy metabolism, the generation of reactive oxygen species (ROS), and dysfunction in calcium handling [5]. In cardiomyocytes, which have high energy demands, mitochondrial dysfunction compromises ATP production through oxidative phosphorylation. Concurrently, it leads to the excessive generation of ROS due to damage in electron transport complexes, particularly Complexes I and III. This creates a detrimental cycle wherein ROS further damages mitochondrial DNA (mtDNA), proteins, and lipids [6, 7]. This oxidative damage accumulates due to the vulnerability of mtDNA to ROS, as it lacks histone protection and is located in proximity to the primary sites of ROS generation. This vulnerability leads to mutations that compromise respiratory chain function and perpetuate energy deficits and oxidative stress [6]. Moreover, depleting antioxidant defenses, particularly affecting cardiomyocytes through altered calcium handling, promotes hypertrophy and triggers apoptosis [8].

Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not encode proteins and are characterized by their length, typically exceeding 200 nucleotides Fig. 1 [9]. These transcripts are a significant component of the non-coding RNA (ncRNA) family and are involved in many cellular processes. In contrast to short non-coding RNAs, such as microRNAs (miRNAs), which are approximately 22 nucleotides in length and modulate gene expression at the post-transcriptional level, long non-coding RNAs (lncRNAs) exhibit a broader range of functions and can influence gene expression at multiple levels, including transcriptional, post-transcriptional, and epigenetic [9, 10]. LncRNAs are known to interact with various biomolecules, including DNA, RNA, and proteins, which allows them to participate in a wide range of biological pathways. They can modulate chromatin function, regulate the assembly and function of nuclear bodies, alter the stability and translation of cytoplasmic mRNAs, and interfere with signaling pathways [11]. These interactions enable lncRNAs to control the flux of genetic information, affecting processes such as chromosome structure modulation, transcription, splicing, mRNA stability, and post-translational modifications [12].

Fig. 1. Subcellular mechanisms of mito-lncRNAs function.

Schematic overview of the diverse regulatory mechanisms of long non-coding RNAs (lncRNAs) across subcellular compartments. In the nucleus, lncRNAs function as scaffolds or guides for chromatin-modifying enzymes, regulating gene expression through cis- and trans-acting mechanisms that alter epigenetic states and transcriptional activity. In the cytoplasm, lncRNAs may act as competing endogenous RNAs (ceRNAs) or molecular sponges, sequestering microRNAs (miRNAs) to modulate target mRNA stability and translation. Within mitochondria, mitochondrial-associated lncRNAs (mito-lncRNAs) regulate mitochondrial homeostasis by stabilizing mitochondrial-encoded mRNAs, maintaining electron transport chain (ETC) complex activity, and modulating mitochondrial quality control processes. Through these compartment-specific mechanisms, mito-lncRNAs influence oxidative phosphorylation, reactive oxygen species (ROS) balance, and mitochondrial integrity—key processes implicated in cardiovascular pathophysiology.

The mechanisms through which lncRNAs) exert their regulatory functions varied. They may function as guides, scaffolds, decoys, or enhancers, thereby influencing gene expression either in proximity (cis-regulation) or at distant locations (trans-regulation) [13]. For instance, some lncRNAs can recruit chromatin-modifying enzymes to specific genomic loci, thereby altering the epigenetic state and affecting gene expression [14]. Others can sequester miRNAs, preventing them from binding to their target mRNAs [15]. LncRNAs have been implicated in various physiological and pathological contexts. They play roles in development, differentiation, and cellular stress responses, and their dysregulation has been associated with a range of human diseases, including CVDs, cancer, and neurological disorders [16]. Due to their tissue-specific and condition-specific expression patterns, lncRNAs are also being explored as potential disease biomarkers and therapeutic targets [11]. Despite the growing understanding of lncRNA functions, many aspects of their biology remain elusive. The advent of high-throughput sequencing technologies has led to the identification of numerous lncRNAs, but functional characterization is challenging due to their complexity and diversity [17]. Recent studies have shown that lncRNAs play crucial regulatory roles in the pathogenesis of CVDs by modulating key cellular processes, including inflammation, apoptosis, fibrosis, and mitochondrial function [18]. Importantly, Mitochondrial long non-coding RNAs (mito-lncRNAs) are key regulators of mitochondrial health and function [19]. Genome-encoded mito-lncRNAs, such as lncND5, lncND6, and lncCytb, stabilize their corresponding mRNAs to ensure proper assembly and activity of electron transport chain complexes, particularly Complex I [20]. Additionally, damaged mtDNA released into the cytoplasm acts as a damage-associated molecular pattern that activates innate immune pathways, including cGAS-STING, TLR9, and NLRP3 inflammasome, triggering chronic inflammation that further propagates cardiovascular pathology when mitochondrial quality control mechanisms like mitophagy become overwhelmed [21]. These mito-lncRNAs influence gene expression through diverse mechanisms such as guiding epigenetic modifiers, scaffolding transcription factors, and acting as molecular sponges for microRNAs, thereby fine-tuning signaling pathways involved in cardiac remodeling, acute myocardial infarction (AMI), and heart failure [22]. In this review, we synthesize current evidence on mitochondrial-associated lncRNAs, delineating their molecular mechanisms, cardiovascular relevance, and emerging translational potential, while highlighting the critical challenges that must be addressed to advance the field toward clinical application.

Mito-lncRNAs classification and functions

Classification of mito-lncRNAs

mito-lncRNAs represent a specialized class of long non-coding RNAs that either originate from mitochondrial DNA (mtlncRNAs) or are nuclear-encoded lncRNAs (nulncRNAs) that are transported into mitochondria to regulate mitochondrial function, biogenesis, and metabolism. Mitochondrial targeting nuclear-encoded lncRNAs are long non-coding RNAs transcribed from nuclear chromosomes that are subsequently imported into mitochondria through specific transport mechanisms to regulate mitochondrial function. These lncRNAs are transported into mitochondria primarily via polynucleotide phosphorylase (PNPase), which recognizes specific sequence motifs and secondary structural features, particularly stem-loop structures with 0–2 nucleotide 3′ overhangs that enhance binding affinity to PNPase’s KH and S1 RNA-binding domains [23]. On the other hand, Mitochondrial DNA-encoded long non-coding RNAs (mtDNA-encoded lncRNAs) are antisense transcripts directly transcribed from the mitochondrial genome that remain localized within mitochondria to regulate mitochondrial gene expression and function. Unlike nuclear-encoded mitochondrial targeting lncRNAs that require import machinery, these mtDNA-encoded lncRNAs are synthesized directly in the mitochondrial matrix from the mitochondrial genome [24, 25]. mtlncRNAs play crucial roles in maintaining mitochondrial homeostasis through diverse molecular mechanisms, including direct protein interactions, epigenetic regulation of mitochondrial genes, and coordination of nuclear-mitochondrial communication [26, 27].

Functions of mito-lncRNAs

The following are mito-lncRNAs displaying crucial roles in mitochondrial physiology (Fig. 2 and Table 1).

Fig. 2. Genomic landscape and regulatory axes of mitochondrial-targeting lncRNAs.

Central to mitochondrial homeostasis is a bidirectional communication network mediated by two distinct classes of long non-coding RNAs (lncRNAs). (Left) Nuclear-Encoded Import: lncRNAs such as MALAT1, SAMMSON, RMRP, GAS5, and H19 are transcribed from nuclear chromosomes and imported into the mitochondrial matrix. This transport is primarily facilitated by PNPase, which recognizes specific stem-loop motifs, and the transmembrane protein MTCH2. Once localized, MALAT1 acts as an epigenetic scaffold to promote OXPHOS gene transcription; SAMMSON interacts with p32 to maintain cristae structural integrity and respiratory capacity; and RMRP associates with GRSF1 to facilitate mtDNA replication and RNA processing. Metabolic fine-tuning is exerted by GAS5, which disrupts the FH-MDH2-CS TCA metabolon to inhibit substrate channeling, while H19 prevents excessive Pink1/Parkin-mediated mitophagy by sequestering eIF4A2. (Right) Mitochondrial-Encoded Signaling: Transcripts originating directly from the mitochondrial genome (mtDNA) function locally or as systemic signals. Antisense lncRNAs lncND5, lncND6, and lncCytB form RNA-RNA duplexes with their respective sense mRNAs to stabilize transcripts and ensure the assembly of Respiratory Complexes I and III. Conversely, lncMDL1 and lncMDL1AS act as retrograde messengers, translocating to the nucleus via HuR/PNPT1 to modulate apoptotic gene networks and p53-mediated stress responses. Finally, lncLIPCAR, a chimeric transcript derived from the CYTB and COX2 loci, is released into the systemic circulation as a diagnostic biomarker for pathological cardiac remodeling.

Table 1.

Genomic origin, mitochondrial localization mechanisms, and primary functions of mito-lncRNAs discussed in this review.

lncRNA	Origin	Import mechanism	Primary function
MALAT1	Nuclear genome-encoded lncRNA	- Exported from nucleus - Imported into mitochondria via: (1) RNA-binding protein HuR (2) Mitochondrial transmembrane protein MTCH2 (3) In some contexts, PNPase-mediated import is implicated	- Binds mtDNA loci (D-loop, MT-CO2, MT-ND3, MT-CYTB) - Regulates CpG methylation of mtDNA - Promotes transcription of OXPHOS genes - Maintains ATP production and mitochondrial biogenesis - Regulates: • Mitochondrial fusion/fission balance • Mitophagy • ROS homeostasis
SAMMSON	Nuclear-encoded lncRNA	- Interacts with mitochondrial protein p32 - Facilitates p32 targeting to mitochondria - Coordinates mitochondrial and cytosolic protein synthesis - Does not rely strictly on classical RNA import via PNPase	- Enhances mitochondrial biogenesis - Maintains respiratory chain function - Promotes Complex I activity - Preserves cristae structure - Supports mitochondrial translation - Regulates mitochondrial structural integrity
RMRP	Nuclear genome–encoded lncRNA	- Exported from nucleus via HuR - Imported into mitochondria via PNPase - Retained in mitochondrial matrix by binding to GRSF1	- Catalytic RNA component of mitochondrial RNase MRP complex - Participates in: • mtDNA replication initiation • RNA processing • Ribosomal RNA maturation - Maintains: • mtDNA copy number • Oxygen consumption rate • ATP production
GAS5	Nuclear genome–encoded lncRNA	- Translocates into mitochondria under metabolic stress - Direct mitochondrial localization - Protein-facilitated transport	- Regulates TCA cycle flux - Disrupts FH–MDH2–CS metabolon - Modulates: • SIRT3–MDH2 interaction • Enzyme deacetylation - Reduces mitochondrial metabolic flux - Suppresses mitochondrial fission via Drp1 interaction - Controls energy stress signaling
H19	Nuclear genome–encoded lncRNA	- Translocates to mitochondria - Direct mitochondrial localization	- Regulates mitophagy via: • Pink1/Parkin axis • eIF4A2 binding - Controls VDAC1 expression - Modulates: • ER–mitochondria contact • Mitochondrial calcium levels • ROS production - Precursor of miR-675: • Regulates CaMKIIδ (hypertrophy) • Targets VDAC1 (apoptosis control)
lncND5	- Mitochondrial genome–encoded - Antisense transcript complementary to MT-ND5 mRNA	- Synthesized directly in the mitochondrial matrix - Can be exported to the cytoplasm via TDP-43	- Forms RNA-RNA duplex with ND5 mRNA (nt 1086–1159) - Stabilizes ND5 transcript - Maintains Complex I assembly and activity - Regulates cardiolipin-mediated Complex I stability - Controls ROS levels - Suppresses excessive mitophagy
lncND6	- Mitochondrial genome–encoded - Antisense transcript of MT-ND6 - Transcribed from a heavy strand	- Synthesized in the mitochondrial matrix - Processing regulated by MRPP1 - Potential shuttling to nucleus (retrograde signaling)	- Stabilizes ND6 mRNA - Ensures Complex I assembly - Compensates for ND6 non-polyadenylation - Maintains mitochondrial gene expression stability
lncCytB	- Mitochondrial genome–encoded - Antisense transcript of the CYTB gene	- Synthesized directly in mitochondria - Binds mtDNA regions	- Stabilizes CYTB mRNA - Maintains Complex III activity - Protects mtDNA via nucleoid formation - Regulates mitochondrial chromatin organization - Prevents mtDNA damage under hyperglycemia - Controls ROS production
MDL1 & MDL1AS	- Encoded in the mitochondrial D-loop region - Heavy and light strand transcripts	- Synthesized in mitochondria - Exported to nucleus via: • HuR • PNPT1	- Retrograde signaling mediators - Regulate nuclear genes involved in: • Cell cycle • Apoptosis • Stress responses - MDL1: • Inhibits p53 nuclear translocation - MDL1AS: • Modulates oxidative phosphorylation
LIPCAR	- Mitochondrial-derived transcript - Discontinuous antisense mapping to: • CYTB (5′) • COX2 (3′)	- Mitochondrial origin - Released into circulation via extracellular vesicles	- Reflects mitochondrial stress - Associated with: • OXPHOS impairment • ROS elevation

lncMALAT1

Mitochondrial MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) is a nuclear-encoded long non-coding RNA that is transported into mitochondria via the RNA-binding protein HuR and mitochondrial transmembrane protein MTCH2, where it functions as an epigenetic regulator of mitochondrial metabolism and function [28]. MALAT1 directly interacts with several mitochondrial DNA loci, including the D-loop, MT-CO2, MT-ND3, and MT-CYTB genes. This interaction inhibits CpG methylation and enhances the transcription of genes involved in oxidative phosphorylation, thereby sustaining ATP production, mitochondrial biogenesis, and respiratory function [29]. The deficiency of MALAT1 results in several mitochondrial abnormalities, including a reduced mtDNA copy number, decreased oxidative phosphorylation, impaired mitophagy, and the activation of mitochondrial apoptotic pathways. This underscores its essential function as a nucleus-to-mitochondria messenger that coordinates mitochondrial homeostasis and cellular metabolism [30].

lncSAMMSON

Mitochondrial SAMMSON (Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA) is a long non-coding RNA encoded by the nucleus, expressed specifically in melanoma cells. It plays a crucial role in regulating mitochondrial metabolism and homeostasis by interacting with the mitochondrial protein p32 [31]. lncSAMMSON directly binds to p32, a key regulator of mitochondrial metabolism. This interaction promotes the proper targeting and localization of p32 to mitochondria. Once there, p32 enhances mitochondrial biogenesis, improves respiratory chain function, and increases oxidative phosphorylation capacity [32]. The lncSAMMSON-p32 complex is crucial for maintaining mitochondrial structure. It helps support proper cristae formation and matrix density. When lncSAMMSON is silenced, it leads to severe mitochondrial dysfunctions. These include fragmented cristae, lower membrane potential, reduced Complex I activity, and impaired spare respiratory capacity [33].

In vascular physiology, lncSAMMSON appears to influence vascular smooth muscle cell (VSMC) physiology, which is an integral part of cardiovascular physiology. In normal conditions, lncSAMMSON likely helps maintain vascular wall integrity by modulating VSMC proliferation and activity, in part through its interaction with pre-miR-130a. By restraining the maturation of miR-130a, lncSAMMSON may prevent excessive VSMC growth, thereby supporting a balanced state of vascular remodeling and vessel-wall stability. This suggests that in the healthy circulation, lncSAMMSON contributes to the controlled behavior of VSMCs, which are central for regulating vascular tone, structure, and overall cardiovascular function [34]. However, it is important to emphasize that this study did not demonstrate a direct role of lnclncSAMMSON in established CVDs such as atherosclerosis, hypertension, myocardial infarction, or heart failure. Instead, the available evidence is limited to intracranial aneurysms (Table 2).

Table 2.

Disease-specific expression patterns and mitochondrial mechanisms of mito-lncRNAs in cardiovascular diseases.

lncRNA	Disease context	ExpressionChange (as stated)	Mitochondrial-related mechanism (as described)	Downstream molecular axis (if specified)	Reported functional effect
LIPCAR	Acute myocardial infarction (AMI) – acute phase	↓ Downregulated	Reflects mitochondrial stress and altered RNA processing	Not specified	Associated with the acute injury phase
LIPCAR	Post-AMI remodeling (chronic phase)	↑ Upregulated	Associated with impaired oxidative phosphorylation and increased ROS	Not specified	Promotes fibroblast activation, ECM remodeling, and cardiomyocyte apoptosis
LIPCAR	Chronic heart failure	↑ Elevated (circulating)	Reflects mitochondrial dysfunction	Not specified	Predicts adverse remodeling and cardiovascular mortality
MALAT1	AMI (microvascular endothelial cells)	↑ Upregulated	Regulates mitochondrial fusion dynamics	MALAT1–miR-26b-5p–Mfn1	Maintains fusion; sustained overexpression leads to ATP impairment and ROS increase
MALAT1	DCM	↑ Upregulated	Promotes mitochondrial fission via Drp1 phosphorylation	MALAT1–miR-185-5p–RhoA/ROCK–Drp1	Increases ROS and apoptosis
MALAT1	Septic myocardial injury	↑ Elevated	Impairs mitophagy	MALAT1–miR-146a–TLR4/NF-κB/MAPK	Accumulation of dysfunctional mitochondria, increased oxidative stress, and apoptosis
RMRP	Cardiac fibrosis	↑ Upregulated	Indirect mitochondrial relevance; promotes fibroblast activation	RMRP–miR-613	Increased fibroblast proliferation and collagen accumulation
RMRP	CAD	↑ Elevated (serum)	Not mechanistically defined in mitochondria	Not specified	Diagnostic and prognostic biomarker [correlates with SYNTAX score and major adverse cardiovascular events （MACEs)]
RMRP	Doxorubicin-induced cardiotoxicity	↓ Downregulated	Preserves mitochondrial integrity when restored	RMRP–PFN1–p53	Reduces apoptosis and oxidative stress
H19	Obesity-related cardiac dysfunction	↓ Downregulated	Regulates mitophagy	H19–eIF4A2–PINK1/Parkin	Prevents excessive mitophagy and mitochondrial depletion
H19	DCM	↓ Downregulated	Regulates mitochondrial apoptosis	H19–miR-675–VDAC1	Reduces cytochrome c release and caspase-3 activation
H19	AMI (early post-MI)	↑ Upregulated	Associated with stress remodeling	H19–YB-1–COL1A1	Promotes fibrosis and adverse remodeling
H19	AMI (protective studies)	Not specified	Suppresses pyroptosis	H19–miR-22-3p–KDM3A	Reduces infarct size and inflammation
H19	Ischemia/Reperfusion (I/R) injury	Not specified	Reduces mitochondrial apoptosis; promotes autophagy	H19–miR-877-3p–Bcl-2; H19–miR-143–ATG7	Decreases apoptosis and oxidative stress
H19	Pressure overload (TAC)	Biphasic (↑early, ↓ late)	Regulates mitochondrial calcium and energetics	H19–miR-675–CaMKIIδ	Limits hypertrophy and preserves function
H19	Endothelial-to-mesenchymal transition (EndMT)	↓ Loss of function	Alters TGF-β signaling	Not specified	Promotes fibrosis when deficient
lncND5	Pulmonary hypertension (hypoxia-induced)	↓ Downregulated	Stabilizes MT-ND5 mRNA; maintains Complex I activity; regulates mitophagy	PINK1–Parkin axis; interaction with HMGCS1	Downregulation increases ROS and mitophagy; restoration improves mitochondrial function

lncRMRP

The mitochondrial RNA component of the RNA-processing endoribonuclease (RMRP) is a nuclear-encoded long non-coding RNA. It is exported from the nucleus by the HuR protein and subsequently imported into mitochondria via PNPase. Upon entry into the mitochondrial matrix, it is retained through its binding to GRSF1 (G-rich RNA sequence-binding factor 1), thereby facilitating its involvement in mtDNA replication and RNA processing [35]. RMRP functions as the catalytic RNA core of the mitochondrial RNase MRP complex. This complex cleaves mitochondrial precursor RNAs and is essential for several cellular processes. These include initiating mtDNA replication, processing ribosomal RNA, and regulating the cell cycle [36]. The presence of GRSF1-RMRP complexes in the mitochondrial matrix is crucial for maintaining mitochondrial respiratory function. GRSF1 silencing reduces RMRP levels in mitoplasts, which leads to impaired oxygen consumption rates [36]. Additionally, it causes decreased ATP turnover, a reduced mtDNA copy number, and compromised oxidative phosphorylation capacity [36]. Loss of RMRP function results in significant mitochondrial dysfunction characterized by disturbed ribosomal biogenesis, reduced expression of mitochondrial genes (mt-ATP6, mt-CO1, mt-CYB), and activation of cellular stress pathways, including mTOR and NF-κB signaling, due to oxidative DNA damage.

Significantly, numerous studies have demonstrated that RMRP plays a role in cardiovascular physiology and pathology, despite its initial characterization being unrelated to cardiac function. In models of cardiac fibrosis, RMRP expression is elevated in hearts subjected to pressure overload and in cardiac fibroblasts treated with angiotensin II. In these contexts, RMRP facilitates fibroblast proliferation, differentiation into myofibroblasts, and collagen deposition by functioning as a molecular sponge for miR613, thereby promoting fibrotic remodeling [37, 38]. In individuals diagnosed with coronary artery disease (CAD), elevated serum levels of RMRP are associated with increased SYNTAX scores and heightened disease severity. Consequently, RMRP has been suggested as a potential diagnostic and prognostic biomarker for major adverse cardiovascular events (MACEs) [37]. Several recent reviews also classify RMRP among lncRNAs implicated in CVDs, underscoring that changes in mitochondrial-localized RMRP can translate into altered myocardial energy metabolism, fibrosis, and coronary-lesion burden, all of which are central to cardiovascular physiology.

lncGAS5

lncRNA GAS5 emerges as a key player at the intersection of mitochondrial metabolism and cardiovascular physiology [39]. Originally described as a growth-arrest–associated transcript that fine-tunes the TCA cycle by disrupting the FH-MDH2-CS metabolon and modulating mitochondrial energy production, GAS5 also influences mitochondrial dynamics through its interaction with Drp1 and other stress-response pathways [40]. In the context of cardiovascular systems, this metabolic tuning translates into broader control over cell survival, energy supply, and structural integrity in both cardiomyocytes and vascular cells, setting the stage for its involvement in a range of heart and vessel disorders [39].

GAS5 is strongly implicated in CAD and atherosclerosis, where reduced circulating and myocardial GAS5 levels correlate with greater plaque burden and disease severity, positioning it as a potential biomarker and cardioprotective factor [41]. In endothelial progenitor cells and ischemic hearts, GAS5 helps maintain vascular repair capacity by promoting proliferation, migration, and angiogenesis while limiting apoptosis and ferroptosis, thereby supporting coronary perfusion and tissue resilience [42]. In parallel, GAS5 restrains maladaptive remodeling in the vessel wall by suppressing VSMC proliferation, which helps prevent excessive neointima formation and preserves normal vascular tone and architecture [43].

Beyond the blood vessels, GAS5 shapes myocardial function and electrical stability. In models of myocardial ischemia-reperfusion injury, GAS5 acts through miR-532-5p to regulate the PI3K/AKT pathway, thereby limiting cardiomyocyte apoptosis and preserving pump function [40]. In hypertrophic and fibrotic settings, GAS5 attenuates pressure-overload–induced cardiac fibrosis, improves ejection fraction, and restrains isoproterenol-driven remodeling, indicating a protective role against structural deterioration [44]. Recent research has intriguingly associated GAS5 with atrial electrical remodeling and an increased susceptibility to arrhythmias. This suggests that its mitochondrial and transcriptional effects may extend beyond energy metabolism to include the regulation of ion channels [45]. Collectively, these findings characterize GAS5 as a multifunctional regulator across various cardiovascular diseases, including CAD, atherosclerosis, myocardial infarction, hypertrophy, fibrosis, and arrhythmia. This underscores its integrative roles in maintaining the metabolic, structural, and electrical homeostasis of the heart and circulatory system.

lncND5

Mitochondrial lncND5 is a mitochondrial genome-encoded long non-coding RNA that serves as the antisense transcript complementary to mitochondrial ND5 mRNA. LncND5 is the most prevalent mito-lncRNA, constituting 58% of the levels of its mRNA counterpart. It plays a pivotal role in maintaining Complex I activity and regulating mitophagy. LncND5 operates by forming intermolecular RNA-RNA duplexes with MT-ND5 mRNA at nucleotides 1086–1159 bp, thereby stabilizing the transcript and ensuring the proper synthesis of the ND5 protein, which is crucial for Complex I assembly and the function of the respiratory chain [46, 47]. Furthermore, lncND5 demonstrates distinct trafficking characteristics, as it can be translocated from the mitochondria to the cytoplasm via TAR DNA-binding protein 43 (TDP-43). In the cytoplasm, it directly interacts with hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) to inhibit mitophagy and thereby maintain cellular homeostasis [20]. The existing literature on lncND5 predominantly focuses on pulmonary hypertension and the biology of pulmonary artery smooth muscle cells (PASMCs). These findings hold significant implications for the broader field of cardiovascular physiology, as they pertain to essential processes such as mitochondrial energy production, ROS signaling, and selective mitochondrial clearance. These processes are also fundamental to the pathophysiology of heart failure, ischemia-reperfusion injury, and systemic vascular dysfunction [47]. Given that lncND5 regulates a fundamental component of the mitochondrial inner membrane (MTND5) and links this regulation to autophagy and metabolic signaling, it is plausible that lncND5 exerts an influence on myocardial and systemic vascular energetics beyond the pulmonary vasculature. However, direct investigations in the heart or in systemic arterial disease remain limited.

lncND6

Mitochondrial lncND6 is a long non-coding RNA encoded by the mitochondrial genome, antisense to ND6 mRNA, constituting 34% of its abundance. It is distinctively transcribed from the heavy strand of mitochondrial DNA, unlike the majority of other mito-lncRNAs. LncND6 operates by forming intermolecular RNA-RNA duplexes with MT-ND6 mRNA, thereby stabilizing the transcript and facilitating the proper synthesis of the ND6 protein necessary for Complex I assembly. This is particularly noteworthy because ND6 mRNA is the sole non-polyadenylated mitochondrial mRNA and may thus necessitate additional stabilization mechanisms [48]. In addition, like other mito-lncRNAs, lncND6 exhibits the capacity for intracellular trafficking and can shuttle between mitochondria and the nucleus to participate in retrograde signaling pathways that coordinate mitochondrial-nuclear communication [19]. The regulation of the processing and maturation of lncND6 is mediated by mitochondrial RNase P protein 1 (MRPP1), which affects the abundance of this lncRNA transcript. Disruption of this processing can impact the stability of mitochondrial gene expression and the function of the respiratory chain [19, 20].

lncCytB

Mitochondrial lncCytB is a long non-coding RNA encoded by the mitochondrial genome that functions as an antisense transcript to cytochrome B (CYTB) mRNA. It accounts for 14% of the abundance of its mRNA counterpart and is essential for maintaining mitochondrial genomic stability and the function of Complex III [49]. LncCytB creates intermolecular RNA-RNA duplexes with MT-CYTB mRNA to stabilize the transcript and support proper cytochrome B protein synthesis for Complex III assembly. Additionally, it acts as a protector of mtDNA by forming nucleoids and organizing chromatin [50]. In conditions like hyperglycemia in diabetic retinopathy, lncCytB is significantly reduced by over 50%. This causes impaired mtDNA packaging, increased sensitivity to micrococcal nuclease, fewer protective nucleoids, and greater susceptibility to mtDNA damage [51]. The regulatory function of lncCytB extends beyond the stabilization of transcripts; it also engages directly with various regions of mitochondrial DNA, contributing to the maintenance of proper chromatin architecture. This is demonstrated by the reduced mtDNA occupancy during hyperglycemic stress, which compromises mitochondrial genome integrity. Functionally, lncCytB downregulation leads to reduced CYTB gene transcription, decreased Complex III activity, impaired oxygen consumption, increased mitochondrial ROS production, and compromised mitochondrial respiration. Its overexpression ameliorates these defects and prevents hyperglycemia-induced mitochondrial dysfunction [25, 51]. The clinical significance of lncCytB is evident in diabetic retinopathy, where its reduction contributes to the self-perpetuating vicious cycle of mitochondrial dysfunction and oxidative stress that characterizes this diabetic complication.

lncMDL1 and lncMDL1AS

Mitochondrial MDL1 and MDL1AS are long non-coding RNAs encoded in the mitochondrial D-loop region that function as novel retrograde signaling messengers mediating mitochondria-to-nucleus communication and cancer biology regulation. MDL1 spans positions 15,954-576 on the heavy strand, while MDL1AS spans positions 16,024-407 on the light strand, and both are classified as long transcription initial RNAs (ltiRNAs) that serve as precursors to transcription initiation RNAs (tiRNAs) [52]. These mito-lncRNAs have functional importance as they can move from mitochondria to the nucleus, a process mediated by HuR and PNPT1 proteins. Once in the nucleus, they influence networks of genes that control the cell cycle, apoptosis, and responses to stress [53]. These findings highlight that MDL1/MDL1AS are central regulators of mitochondrial–nuclear crosstalk and metabolic fidelity, positioning them as potential players in stress-responsive tissues such as the heart and vasculature.

However, direct experimental studies linking MDL1 or MDL1AS to cardiovascular physiology or overt heart disease are currently limited. Recent reviews of mitochondrial-encoded non-coding RNAs note that MDL1AS downregulation broadly reduces mitochondrial oxidative phosphorylation and metabolic capacity across cell types, underscoring its importance for energetically demanding organs, including the heart. However, this is framed as mechanistic and extrapolated rather than tested in cardiovascular models [16]. In collections of mito-lncRNAs relevant to cardiovascular medicine, MDL1 and MDL1AS are mentioned mainly in the context of cancer prognosis and mitochondrial metabolism, not yet in dedicated heart-failure, ischemia, or atherosclerosis-focused work.

lncLIPCAR

Mitochondrial LIPCAR (Long Intergenic Noncoding RNA Predicting Cardiac Remodeling, also known as uc022bqs.1) is a putative mitochondrial genome-encoded long non-coding RNA that serves as a powerful circulating biomarker for CVD [54]. LIPCAR features a distinctive discontinuous structure: its 5′ half (nucleotides 1–392) is antisense to the mitochondrial CYTB gene, while its 3′ half (nucleotides 385–781) is antisense to the mitochondrial COX2 gene. These halves are separated by roughly half of the mitochondrial genome, giving it a unique structural arrangement [54, 55]. Furthermore, as a mitochondrial-derived lncRNA, LIPCAR likely functions by regulating mitochondrial pathways, including inflammasome activation and oxidative phosphorylation.

lncH19

Mitochondrial H19 is a nuclear-encoded long non-coding RNA that localizes to mitochondria, where it plays a crucial role in regulating mitochondrial function, mitophagy, and cellular metabolism. H19 modulates mitophagy by inhibiting the Pink1/Parkin signaling pathway. It achieves this by directly binding to eIF4A2, a eukaryotic translation initiation factor, thereby inhibiting the translation of Pink1 mRNA. This intervention mitigates excessive mitophagy and contributes to the preservation of mitochondrial respiratory function [56, 57]. Additionally, H19 influences endoplasmic reticulum-mitochondria contact sites by regulating VDAC1 expression. When H19 is inhibited, VDAC1 levels rise, leading to increased ER-mitochondria coupling via more IP3R-VDAC1 contacts. This results in higher mitochondrial calcium levels, increased mitochondrial ROS (mtROS) production, and decreased ATP synthesis and respiratory chain complex gene expression [58].

Mito-lncRNAs in cardiovascular disease pathogenesis

Mito-lncRNAs represent a critical regulatory class of transcripts that originate from either the nuclear or mitochondrial genomes to maintain cardiovascular homeostasis. In the high-energy environment of the heart, mito-lncRNAs ensure the stability of the electron transport chain and the tricarboxylic acid (TCA) cycle, preventing the metabolic collapse and oxidative stress that characterize heart failure (Fig. 3).

Fig. 3. Mechanisms of mito-lncRNAs in CVDs.

a lncLIPCAR: A chimeric mito-lncRNAs (CYTB-COX2) packaged into extracellular vesicles post-myocardial infarction (AMI). High levels indicate mitochondrial stress, promote ROS and fibrosis, and serve as a prognostic biomarker for heart failure. b lncMALAT1: Nuclear-encoded lncRNA imported into mitochondria. In AMI, it regulates Mfn1 via miR-26b-5p to modulate fission/fusion. In diabetic cardiomyopathy, it drives Drp1-mediated fission by sponging miR-185-5p. In sepsis, it inhibits protective mitophagy by suppressing miR-146a. c lncRMRP: In fibrosis/CAD, RMRP sponges miR-613 to de-repress pro-fibrotic genes. Conversely, in doxorubicin cardiotoxicity, it protects mitochondria by modulating the PFN1/p53 axis to reduce apoptosis. d lncH19: Context-dependent roles. In metabolic disease, H19 downregulation triggers excessive PINK1-Parkin mitophagy (via eIF4A2) or apoptosis (via VDAC1/miR-675). Post-AMI, H19 upregulation drives fibrosis via YB-1, while in hypertrophy, H19 protects against remodeling by repressing CaMKIIδ via miR-675 and preventing EndMT. e lncND5: Stabilizes ND5 mRNA and Complex I. Hypoxia-induced downregulation (e.g., in pulmonary hypertension) destabilizes Complex I, increases ROS, and triggers excessive mitophagy/proliferation. Cytoplasmic lncND5 also regulates metabolism via HMGCS1.

lncLIPCAR

Cardiac remodeling and the progression to chronic heart failure following AMI are significant contributors to cardiovascular morbidity and mortality. These conditions are characterized by maladaptive alterations in left ventricular geometry, extracellular matrix deposition, and a decline in contractile function. Emerging evidence implicates mito-lncRNAs in these processes, most notably lncLIPCAR, a discontinuously encoded transcript derived from the mitochondrial CYTB and COX2 loci [59]. LIPCAR is produced through a mechanism similar to trans-splicing, which joins two antisense segments. The first segment, the 5′ half (nt 1–392), aligns with the mitochondrial CYTB gene. The second segment, the 3′ half (nt 385–781), corresponds to cytochrome COX2, with the intervening mitochondrial genome sequences excised during processing [54]. Circulating LIPCAR levels exhibit a biphasic pattern post-AMI; they were initially downregulated during acute injury, followed by sustained upregulation during the chronic remodeling phase. Mechanistically, elevated LIPCAR reflects increased mitochondrial stress and altered RNA processing in cardiomyocytes and is packaged into large extracellular vesicles for release into the circulation [59, 60]. Functionally, LIPCAR dysregulation correlates with impaired oxidative phosphorylation and increased ROS generation, promoting fibroblast activation, extracellular matrix remodeling, and cardiomyocyte apoptosis [61]. Clinically, high plasma LIPCAR levels strongly predict adverse left ventricular remodeling, with an impressive accuracy (AUC = 0.985). Additionally, LIPCAR independently forecasts cardiovascular mortality (HR ≈ 32), surpassing traditional biomarkers like NT-proBNP. This highlights its crucial role in the development and prognosis of heart failure following a heart attack [60].

lncMALAT1

lncRNA MALAT1 drives cardiovascular pathology by disrupting mitochondrial quality control through intertwined fission-fusion and autophagy pathways. Nuclear-encoded mito-lncRNAs like MALAT1 are imported into mitochondria by PNPase, where they bind mtDNA regions (e.g., the D-loop and MT-ND3) to promote mitochondrial gene transcription and maintain ATP production [19, 26, 62]. In the aftermath of AMI, MALAT1 is strongly upregulated in microvascular endothelial cells at the infarct border, where it sequesters miR-26b-5p to de-repress Mitofusin-1 (Mfn1). This MALAT1-miR-26b-5p-Mfn1 axis preserves mitochondrial fusion and prevents excessive fragmentation. However, sustained MALAT1 overexpression exhausts adaptive mitochondrial remodeling, leading to impaired ATP generation, enhanced mtROS release, and endothelial apoptosis. MALAT1 knockdown restores microvascular perfusion and angiogenesis by rebalancing fission and fusion dynamics and reducing oxidative stress, underscoring its pivotal role in post-MI vascular repair [30].

Similarly, in diabetic cardiomyopathy (DCM), MALAT1 exacerbates cardiomyocyte injury by promoting mitochondrial fission through the RhoA/ROCK–Drp1 pathway. High-glucose conditions induce MALAT1 expression, which functions as a competing endogenous RNA (ceRNA) for miR-185-5p, thereby relieving RhoA from miRNA suppression. Activated RhoA enhances Drp1^S616^ phosphorylation, shifting mitochondrial dynamics toward fission, collapsing mitochondrial membrane potential, increasing ROS production, and triggering caspase-3–mediated apoptosis. Inhibition of MALAT1 or ROCK mitigates these effects, restoring mitochondrial morphology and function and reducing cardiomyocyte death in diabetic models [63].

Moreover, during septic myocardial injury, MALAT1 impairs protective mitophagy by downregulating miR-146a, which targets the TLR4/NF-κB/MAPK axis. Elevated MALAT1 in lipopolysaccharide-treated cardiomyocytes suppresses miR-146a, inhibiting mitochondrial autophagy and causing accumulation of dysfunctional mitochondria and oxidative damage. Silencing MALAT1 elevates miR-146a, reactivates mitophagy, stabilizes mitochondrial membrane potential, decreases ROS, and attenuates inflammation and apoptosis via suppression of TLR4/NF-κB/MAPK signaling. Thus, MALAT1 malfunction orchestrates a cascade of mitochondrial dysregulation, including excessive fission, autophagy blockade, ROS overproduction, and cell death, across diverse cardiovascular disease contexts [64].

lncRMRP

lncRNA RMRP has been directly studied in cardiac fibrosis, CAD, hypoxic cardiomyocyte injury, and doxorubicin-induced cardiotoxicity.

Cardiac fibrosis

In models of cardiac fibrosis induced by pressure overload and angiotensin II, the expression of RMRP is markedly upregulated in fibrotic myocardium and activated cardiac fibroblasts. In rats subjected to abdominal aortic banding, RMRP levels were found to be elevated in fibrotic cardiac tissue compared to sham controls [38].

Mechanistically, RMRP acts as a ceRNA that sponges miR-613, thereby preventing miR-613 from suppressing pro-fibrotic target genes. When RMRP is knocked down using siRNA in angiotensin II-stimulated cardiac fibroblasts, miR-613 levels increase, leading to reduced fibroblast proliferation as shown by CCK-8 and EdU incorporation assays. This also results in decreased myofibroblast differentiation, indicated by reduced α-SMA expression, and diminished collagen accumulation, evidenced by lower levels of COL1A1 and COL3A1 mRNA. Luciferase reporter and MS2-RIP assays confirmed direct binding between RMRP and miR-613. Importantly, co-transfection of miR-613 inhibitor reversed the anti-fibrotic effects of RMRP knockdown, confirming that miR-613 is the key downstream effector of RMRP’s pro-fibrotic actions [38, 65].

CAD

Extending beyond cardiac fibrosis, RMRP also plays a significant role in CAD. A 2024 clinical study of 219 CAD patients who underwent coronary angiography demonstrated that serum RMRP levels are significantly elevated in CAD patients compared to healthy controls and correlate with disease severity [37].

The diagnostic accuracy of RMRP was substantial, with ROC curve analysis showing an AUC of 0.882, a sensitivity of 87.5%, and a specificity of 72.3% for detecting CAD. Furthermore, multivariate logistic regression identified age, LDL-C, RMRP, and rest LVEF as independent factors affecting SYNTAX scores (a measure of coronary lesion complexity). During follow-up, 19 MACEs occurred in the high-RMRP group, compared with 9 in the low-RMRP group. Multivariate Cox regression confirmed that age, SYNTAX score, rest LVEF, and RMRP were independent risk factors for MACEs. These data establish RMRP as a clinically useful biomarker for CAD diagnosis and prognosis [37].

Doxorubicin-induced cardiotoxicity

Contrary to its pro-fibrotic and pro-injury roles in the previously mentioned cardiac conditions, RMRP demonstrates cardioprotective effects in the context of doxorubicin-induced cardiomyopathy. Specifically, RMRP expression is downregulated in cardiomyocytes treated with doxorubicin [66]. RMRP upregulation protects against doxorubicin toxicity by modulating the profilin-1 (PFN1)/p53 axis. RMRP overexpression reduced doxorubicin-induced apoptosis, oxidative stress, and mitochondrial dysfunction. The protective effect involves suppressing p53-mediated apoptotic pathways, indirectly preserving mitochondrial integrity. This study suggests RMRP may serve as a therapeutic target and biomarker for anthracycline cardiotoxicity [66].

lncH19

Obesity

lncRNA H19 plays a pivotal role in mitochondrial quality control across diverse cardiovascular and vascular diseases. In obesity-related cardiac disease, H19 downregulation drives mitochondrial respiratory dysfunction through a well-characterized molecular cascade. Palmitic acid exposure and metabolic stress induce DNA methylation of the H19 promoter by upregulating DNMT3b, thereby suppressing H19 transcription. This epigenetic silencing of H19 has profound consequences for mitochondrial homeostasis [56]. Mechanistically, H19 normally binds to eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), preventing eIF4A2 from associating with PINK1 mRNA and thereby suppressing PINK1 protein translation. When H19 is downregulated in obesity models, eIF4A2 is released, enabling PINK1 mRNA translation and leading to excessive PINK1-PRKN (Parkin)-mediated mitophagy. This aberrant mitophagy cascade results in a dramatic reduction in mitochondrial number (approximately 40%–60% loss), mitochondrial shrinkage, and severe impairment of respiratory capacity, as evidenced by decreased basal respiration, maximal respiration, and ATP production [56]. In leptin-deficient mice, this H19 deficiency-driven mitochondrial depletion directly translates to cardiac dysfunction, characterized by an altered E/A ratio (left ventricular diastolic dysfunction) and increased left ventricular end-diastolic dimension. Remarkably, cardiomyocyte-specific restoration of H19 expression via AAV-mediated gene therapy rescued mitochondrial complex III, IV, and V levels. It also restored mitochondrial mass and respiratory function, completely normalizing cardiac functional parameters. The findings indicate that the downregulation of H19, which leads to excessive mitophagy, constitutes a primary pathogenic mechanism in cardiac metabolic disorders induced by obesity [56].

DCM

Analogous to obesity-related cardiac dysfunction, dilated cardiomyopathy (DCM) is characterized by the downregulation of H19. However, the subsequent pathogenic mechanism in DCM shifts towards mitochondrial-mediated apoptosis, as opposed to excessive mitophagy. Streptozotocin-induced diabetic rats and high-glucose-exposed cardiomyocytes both exhibit significant H19 downregulation, which correlates with increased cardiomyocyte apoptosis and impaired left ventricular function [67]. In this context, H19 serves as the precursor for miR-675, which directly targets the 3′-UTR of voltage-dependent anion channel 1 (VDAC1), a critical mitochondrial outer membrane protein that controls cytochrome c release during apoptosis. When H19 is downregulated, the production of miR-675 decreases, resulting in the upregulation of VDAC1. The elevated levels of VDAC1 enhance the permeability of the mitochondrial outer membrane, thereby facilitating the release of cytochrome c into the cytoplasm, the activation of caspase-3, and an increased Bax/Bcl-2 ratio. These processes are indicative of intrinsic (mitochondrial) apoptosis. Experimental overexpression of H19 in diabetic models reduced VDAC1 expression, suppressed cardiomyocyte apoptosis (as evidenced by TUNEL staining), decreased cleaved caspase-3 and LDH release, and improved cardiac contractile function. Conversely, co-overexpression of H19 and VDAC1 nullified the anti-apoptotic effects of H19, thereby confirming that VDAC1 serves as the principal downstream effector responsible for mediating H19’s protective effects on mitochondrial integrity in DCM [67].

AMI

In contrast to the consistent downregulation observed in metabolic diseases, H19’s role in AMI is notably complex and biphasic, with temporal and cell-type-specific expression patterns determining whether H19 is protective or pathogenic.

Early post-AMI upregulation: pro-fibrotic and hypertrophic pathology

Following ligation of the left anterior descending artery in mice, there is a significant upregulation of H19 expression within the infarct zone, peaking at day 4 post-myocardial infarction (MI). This upregulation, primarily observed in cardiac fibroblasts and endothelial cells, contributes to maladaptive cardiac remodeling through its interaction with Y-box-binding protein 1 (YB-1) [68]. Under hypoxic conditions, H19 directly binds to YB-1 protein, sequestering it and preventing YB-1 from suppressing Collagen 1A1 (COL1A1) transcription. This de-repression of COL1A1, along with upregulation of COL1A2, COL3A1, fibronectin, and other extracellular matrix genes, results in severe cardiac fibrosis, dilation, and chamber enlargement. Mice overexpressing H19 via AAV9 delivery exhibited dramatically increased end-diastolic and end-systolic volumes, larger infarct areas, enhanced collagen deposition (confirmed by Masson’s trichrome staining), and elevated expression of fibrosis markers (α-SMA, periostin, vimentin) at post-MI day 4 [68]. Conversely, genetic ablation of H19 using CRISPR-Cas9 ameliorated post-MI cardiac remodeling, resulting in a smaller infarct size, reduced fibrosis area, less collagen content, improved ejection fraction and fractional shortening, and decreased expression of ECM genes. These data demonstrate that H19 upregulation post-MI exacerbates fibrotic remodeling through YB-1 antagonism and ECM dysregulation [68].

Protective roles: anti-apoptotic and anti-inflammatory actions

Contrary to its pro-fibrotic role in early post-myocardial infarction (MI) remodeling, other studies have demonstrated the protective functions of H19 in the AMI context. H19 mitigates cardiomyocyte pyroptosis, an inflammatory form of cell death, by modulating the PBX3/CYP1B1 axis, thereby reducing inflammasome activation. Additionally, H19 functions as a competing endogenous RNA (ceRNA) by sponging miR-22-3p, which leads to the upregulation of KDM3A, a histone demethylase involved in chromatin remodeling. This process results in a reduction of infarct size, enhancement of cardiac performance, and alleviation of cardiac fibrosis through anti-apoptotic and anti-inflammatory mechanisms [68]. The seemingly contradictory roles of H19 likely reflect temporal dynamics (early versus late post-myocardial infarction expression), cell-type specificity (fibroblasts versus cardiomyocytes), and subcellular localization, thereby underscoring the complexity of long non-coding RNA biology in the context of tissue injury.

Ischemia/reperfusion injury

Paralleling its protective roles in AMI, H19 protects cardiomyocytes from mitochondrial apoptosis during myocardial ischemia/reperfusion (I/R) injury by sponging miR-877-3p, which otherwise suppresses Bcl-2. H19 overexpression increases Bcl-2 levels, reduces mitochondrial cytochrome c release, and decreases caspase-3 activation, thereby limiting apoptotic cell death and reducing infarct size. Additionally, H19 enhances nucleolin stability, thereby supporting mitochondrial resilience under hypoxic stress [69]. Moreover, H19 modulates autophagy during I/R by sequestering miR-143, which normally targets autophagy-related gene 7 (ATG7). By de-repressing ATG7, H19 promotes autophagic flux, facilitating the clearance of damaged mitochondria and cellular debris, thereby reducing oxidative stress and apoptosis during reperfusion [70].

Cardiac hypertrophy and heart failure

Extending beyond acute ischemic injury, H19 also plays critical roles in chronic pressure-overload cardiac disease. In transverse aortic constriction (TAC) models, H19 shows a biphasic expression pattern: an initial upregulation during the compensated hypertrophy phase (weeks 1–2 post-TAC), followed by significant downregulation during the transition to decompensated heart failure (weeks 4–13) [71, 72]. H19 knockout mice subjected to TAC develop exaggerated cardiac hypertrophy, increased cardiomyocyte size, elevated expression of pro-hypertrophic markers (NPPB and MCIP1.4), and worse cardiac function than wild-type controls. H19 exerts its anti-hypertrophic effects by serving as the precursor to miR-675, which directly targets and represses calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ), a pro-hypertrophic kinase involved in calcium handling and energy metabolism [71–73]. CaMKIIδ regulates mitochondrial calcium uptake and ATP production; excessive activation impairs mitochondrial energetics and promotes hypertrophic growth. By suppressing CaMKIIδ via miR-675, H19 maintains mitochondrial bioenergetic balance and limits pathological hypertrophy. Additionally, H19 promotes angiogenesis by enhancing VEGF and eNOS expression (via miR-181a inhibition), thereby supporting capillary density and oxygen delivery to the hypertrophied myocardium [71]. Therapeutic restoration of H19 in failing hearts via gene therapy prevents and reverses experimental pressure-overload-induced heart failure, thereby improving systolic function and reducing fibrosis, confirming H19’s role as a protective, anti-hypertrophic lncRNA.

Endothelial-to-mesenchymal transition

Beyond cardiomyocytes, H19 regulates cardiac endothelial cell fate transitions that contribute to fibrosis and vascular dysfunction. In mouse models with H19 loss-of-function (H19^ΔICR/H19⁺), the H19 lncRNA is destabilized, whereas miR-675 remains intact. These animals develop cardiomyopathy by 6 months of age, characterized by cardiac hypertrophy, fibrosis, and increased expression of disease markers [74]. Transcriptomic analysis of cardiac endothelial cells from H19-deficient mice revealed dysregulated genes, many of which are associated with endothelial-to-mesenchymal transition (EndMT). EndMT is a process in which endothelial cells lose endothelial markers, such as CD31, and acquire mesenchymal markers, including α-SMA and Vimentin. H19-deficient endothelial cells show a modest but significant increase in cells co-expressing endothelial and mesenchymal markers, indicating a transitional phenotype. Forced expression of H19 in primary endothelial cells prevents activation of mesenchymal gene expression, demonstrating H19’s role in maintaining endothelial identity [74]. Mechanistically, H19 deficiency results in a 50% reduction in TGF-β receptor expression, thereby disrupting TGF-β signaling, a key pathway that regulates EndMT and mitochondrial function. Because EndMT contributes to perivascular fibrosis, myofibroblast accumulation, and impaired microvascular perfusion, H19’s regulation of this process represents another link between lncRNA dysfunction and cardiac pathology driven by vascular mitochondrial abnormalities [74].

lncND5

In pulmonary hypertension (PH), hypoxia-induced downregulation of mitochondrial lncND5 triggers a pathogenic cascade characterized by excessive mitophagy and ROS overproduction. Under normoxic conditions, lncND5 maintains respiratory complex I integrity by directly binding MT-ND5 mRNA at nucleotides 1086-1159, thereby stabilizing the transcript and ensuring robust complex I activity. Additionally, lncND5 preserves complex I assembly by regulating cardiolipin (CL), a critical phospholipid of the inner mitochondrial membrane. However, when PASMCs are exposed to hypoxia, lncND5 expression is markedly suppressed, leading to MT-ND5 mRNA destabilization, reduced complex I activity, and a surge in mtROS release. This oxidative burst activates the PINK1-Parkin mitophagy pathway, leading to excessive mitochondrial elimination and severe energetic failure that paradoxically drives PASMC proliferation rather than apoptosis, a hallmark of pulmonary vascular remodelling [47].

Beyond its mitochondrial role, lncND5 exerts anti-proliferative effects in the cytoplasm through a novel extra-mitochondrial mechanism. lncND5 is transported from the mitochondria to the cytoplasm via TAR DNA-binding protein 43 (TDP-43), where it directly interacts with hydroxymethylglutaryl-CoA synthase 1 (HMGCS1), an enzyme involved in ketogenesis and lipid metabolism. This interaction suppresses mitophagy through pathways independent of complex I, providing dual mitochondrial and cytoplasmic brakes on pathological PASMC proliferation. Under hypoxia, lncND5 depletion disrupts both mitochondrial (complex I-ROS-PINK1) and cytoplasmic (HMGCS1) regulatory axes, synergistically promoting excessive mitophagy, enhanced cell proliferation, and pulmonary arterial wall thickening [47].

Therapeutic restoration of lncND5 in Sugen5416 plus hypoxia (SuHx)-induced PH mouse models reversed these pathological changes, reducing mitophagy markers, normalizing mtROS levels, restoring mitochondrial respiratory capacity, and ameliorating pulmonary vascular remodeling and right ventricular hypertrophy, as assessed by echocardiography and hemodynamic measurements. These findings establish lncND5 as a central orchestrator of mitochondrial quality control in PH pathogenesis. Its loss drives the transition from adaptive hypoxic responses to maladaptive vascular remodeling by coordinating disruptions in complex I bioenergetics, ROS homeostasis, and mitophagy, positioning lncND5 as a promising therapeutic target for PH [47].

Current challenges and barriers in mito-lncRNAs cardiovascular research and translation

Despite growing interest in mito-lncRNAs as regulators of cardiac mitochondrial homeostasis, their development as diagnostic or therapeutic tools remains in its early stages. Before mito-lncRNAs can be reliably advanced toward clinical translation, several foundational scientific and translational challenges must be addressed. These include technical limitations in detection and quantification, incomplete mechanistic understanding, species-specific variability, and barriers to cardiac- and mitochondrial-targeted delivery (Fig. 4).

Fig. 4. Current challenges and translational barriers in mito-lncRNAs cardiovascular research.

a Cardiac-specific delivery and mitochondrial import barriers. Efficient targeting of mito-lncRNAs to cardiomyocyte mitochondria is hindered by multiple sequential barriers, including cellular uptake, passage through the TOM and TIM complexes, and PNPase-mediated import across the inner membrane. Large transcript size, complex secondary structure, limited capacity of the RNA import machinery, and disease-associated reductions in membrane potential or oxidative damage to import proteins further reduce mitochondrial delivery efficiency. b Limited conservation and model relevance. Many mito-lncRNAs exhibit poor sequence conservation between humans and rodents, and some lack identifiable orthologs in common preclinical models. Rapid evolution of mitochondrial genomes and species-specific regulatory elements limit extrapolation of rodent findings to human cardiomyocytes, underscoring the need for humanized or alternative translational systems. c Inadequate cardiac delivery and off-target effects. Systemic delivery platforms such as AAV vectors, lipid nanoparticles (LNPs), and antisense oligonucleotides (ASOs) face challenges including uneven myocardial transduction, hepatic diversion, immune activation, and off-target uptake in non-cardiac tissues. Local delivery approaches improve myocardial exposure but carry procedural and immunologic risks. d Detection and quantification artifacts as gatekeeping criteria. Mito-lncRNAs candidacy is limited by technical artifacts arising from mitochondrial fraction contamination, low transcript abundance, nuclear mitochondrial DNA segments (NUMTs), and isoform complexity. Rigorous validation strategies—including stringent purification controls, mitochondrial-specific RNA-FISH, and single-molecule assays—are required to distinguish genuine mitochondrial residents from experimental artifacts. e Unclear functional mechanisms and dual localization. Many lncRNAs shuttle between nuclear and mitochondrial compartments, complicating attribution of observed phenotypes to direct mitochondrial actions. Context-dependent signaling and incomplete interactome mapping hinder identification of bona fide mitochondrial effectors. Compartment-specific perturbation tools are essential to define authentic mitochondrial roles. f Regulatory and safety considerations. Therapeutic development is constrained by concerns regarding off-target mitochondrial disruption, immunogenicity of RNA delivery systems, long-term biodistribution, and lack of standardized mito-toxicity assays. Comprehensive safety profiling and regulatory frameworks are necessary prior to clinical translation.

Cardiac-specific delivery and targeting challenges

The poor import efficiency of lncRNAs into cardiac mitochondria stems from cardiomyocytes’ unique architecture and high metabolic demands. First, mito-lncRNAs must cross three successive barriers: the plasma membrane, the outer mitochondrial membrane via the TOM complex, and the inner membrane via TIM channels or PNPase-mediated pathways. Each step is inherently inefficient for large RNA molecules, and there are no dedicated RNA import signals analogous to classic mitochondrial targeting peptides [75]. Once in the cytosol, mito-lncRNAs compete with abundant endogenous mitochondrial RNAs for the limited import machinery. In cardiomyocytes, which devote roughly 30%–40% of cell volume to mitochondria, PNPase and associated carrier proteins (e.g., GRSF1, rhodanese) continuously process and import native transcripts. This high-throughput demand saturates the system, leaving exogenous or overexpressed lncRNAs largely excluded [76]. Moreover, lncRNAs typically exceed 200 nucleotides, far larger than most imported mitochondrial RNAs. Import efficiency declines steeply with cargo size, and secondary structures required for lncRNA function may further hinder translocation through narrow TIM pores or through the central tunnel of PNPase. Engineering stem-loop motifs can improve import of small RNAs but have not reliably rescued full-length lncRNA transport [77]. Finally, disease-associated changes in mitochondrial membrane potential and ROS further disrupt RNA import. In heart failure or ischemia, loss of inner membrane potential impairs TIM-mediated uptake, while oxidative damage to PNPase and carrier proteins reduces their activity, compounding import inefficiency [78]. Together, these factors explain why cardiac mitochondria import exogenous lncRNAs so poorly and underscore the urgent need for novel strategies to enhance mito-lncRNA delivery in cardiovascular research.

Limited conservation and model relevance

Mito-lncRNAs often show low sequence conservation across species, which undermines the relevance of animal models for cardiovascular research. For example, many human mito-lncRNAs lack identifiable orthologs in mice or rats, making it difficult to study their function in common preclinical models. Even when sequence similarity exists, regulatory elements and secondary structures can differ substantially, leading to divergent mitochondrial localization and function between species. This rapid evolutionary turnover means that findings in rodent hearts may not translate to human cardiomyocytes, limiting the predictive power of in vivo studies [79–81].

Moreover, mitochondrial genomes evolve rapidly and harbor human-specific sequences, further complicating cross-species extrapolation. Rodent models of heart disease may lack key components of the mitochondrial import machinery or show altered expression of carrier proteins such as PNPase and GRSF1, thereby altering import efficiency and lncRNA function. Consequently, therapeutic strategies designed to exploit mito-lncRNAs based on rodent data risk failure in human trials, highlighting the urgent need for alternative models or humanized systems to bridge this translational gap [53, 75, 76].

Inadequate cardiac delivery

Cardiac tissue poses unique delivery barriers that severely limit the efficiency of mito-lncRNA therapeutics. Systemic administration of viral vectors such as AAV9, although cardiotropic, results in uneven transduction. This leads to low uptake in fibrotic regions and near intercalated discs, which are critical for maintaining electrical coupling and mitochondrial networks. Moreover, high cardiac output and first-pass hepatic metabolism divert much of the delivered vector or nanoparticle payload away from the heart, necessitating higher doses that exacerbate off-target accumulation in the liver and kidneys and raise safety concerns [80].

Local delivery methods, such as intracoronary infusion or direct myocardial injection, can improve cardiac uptake but also pose risks of ischemic injury, arrhythmias, and tissue damage. Repeated dosing to maintain therapeutic levels is further complicated by the induction of neutralizing antibodies against viral capsids or nanoparticle components, which reduce subsequent delivery efficiency and increase the risk of systemic inflammation and adverse immune reactions. These challenges underscore the need for novel, heart-specific targeting strategies that can safely and reliably deliver mito-lncRNAs to cardiomyocytes in vivo [77, 78].

Detection and quantification artifacts: gatekeeping criteria for mito-lncRNA candidacy

Detection and quantification of mito-lncRNAs in cardiac tissue face substantial technical challenges that fundamentally limit the pool of lncRNAs that can be considered credible therapeutic candidates for cardiovascular disease. Current methods for mitochondrial isolation from the heart—that is, differential centrifugation and density-gradient-based fractionation—are prone to contamination by nuclear and cytoplasmic components, largely due to the high mitochondrial density intertwined with contractile proteins. This contamination can lead to the false assignment of nuclear lncRNAs as mitochondrial residents, skewing both RNA sequencing and qPCR-based quantification and obscuring true mito-lncRNA expression profiles [20, 82, 83].

Additionally, mito-lncRNAs are often expressed at very low copy numbers—sometimes below one molecule per mitochondrion—placing them near the detection limits of standard RNA sequencing and RT-PCR platforms. The presence of nuclear-mitochondrial DNA sequences (NUMTs) in the genome exacerbates this problem, as NUMTs can generate reads that map erroneously to mitochondrial transcripts, leading to artifactual annotation of “mitochondrial” lncRNAs. Furthermore, secondary RNA structures and alternative processing generate multiple transcript isoforms, complicating precise quantification and annotation [20, 82, 84].

To advance rigorous target qualification, the field is developing mitochondrial‑specific RNA‑FISH, single‑molecule RNA‑seq approaches, and stringent mitochondrial‑fractionation protocols with RNA‑contamination controls. These methods are essential for distinguishing genuine mito-lncRNAs from contamination artifacts and for ensuring that only well‑characterized molecules are advanced into preclinical therapeutic pipelines [82, 83].

Unclear functional mechanisms: defining genuine mitochondrial effectors

The functional mechanisms of mito-lncRNAs in cardiomyocytes remain incompletely characterized, limiting their candidacy as mitochondrial-targeted therapeutic agents. Many lncRNAs shuttle between the nucleus and mitochondria, making it difficult to attribute observed phenotypes to mitochondrial-specific actions rather than secondary nuclear effects. For example, MALAT1, a nuclear-scaffold lncRNA involved in splicing regulation, is also detected in cardiac mitochondria under stress, yet its precise mitochondrial interactome and functional role in the organelle remain unclear [20, 73, 83].

Without comprehensive lncRNA–protein interactome maps and compartment‑specific perturbation tools, it is challenging to determine whether a given phenotype stems from direct mito‑lncRNA–protein interactions or from altered nuclear transcription. Moreover, mito‑lncRNAs likely participate in multiple pathways—such as oxidative phosphorylation, apoptosis, and mitochondrial biogenesis—depending on cell type, metabolic state, and disease context. The same lncRNA may act as a scaffold for respiratory complex assembly in healthy hearts but promote pro‑apoptotic signaling under ischemic stress [39, 85, 86].

Conventional loss- and gain-of-function approaches, such as siRNA-mediated knockdown or overexpression, often affect both nuclear and mitochondrial pools, complicating mechanistic interpretation. To address this, the field is moving toward compartment-specific perturbation strategies, including sub-mitochondrial CRISPR-based systems, mitochondrial-targeted antisense oligonucleotides, and RNA-aptamer systems engineered for mitochondrial import. These tools are essential for determining whether a lncRNA exerts a direct mitochondrial effect, thereby qualifying it as a bona fide mitochondrial-targeted therapeutic candidate in cardiovascular disease [85, 87].

Regulatory and safety concerns

Therapeutic use of mito-lncRNAs in the heart raises significant regulatory and safety concerns. RNA-based drugs must undergo rigorous evaluation for off-target effects because lncRNAs can engage multiple unintended pathways, potentially disrupting essential mitochondrial functions in cardiomyocytes. Moreover, the immunogenicity of RNA therapeutics is a significant hurdle; repeated dosing often induces neutralizing antibodies against delivery vehicles (e.g., lipid nanoparticles or viral vectors), triggering inflammatory responses that can exacerbate cardiac injury and undermine treatment efficacy. Regulators require comprehensive data on biodistribution, long-term persistence, and potential integration risks, all of which remain poorly characterized for mito-lncRNAs in cardiovascular settings [78].

Furthermore, the heart’s susceptibility to mitochondrial dysfunction exacerbates safety concerns. Minor perturbations in mitochondrial gene expression or RNA processing can compromise oxidative phosphorylation, potentially leading to arrhythmias or contractile dysfunction. The lack of standardized assays to assess mito-lncRNA toxicity complicates preclinical safety assessments, as conventional cytotoxicity screens often fail to detect mitochondrial-specific effects. Consequently, developers must design specialized safety studies, such as cardiac-specific biodistribution analyses, mitochondrial function assays, and long-term monitoring of cardiac biomarkers, to meet regulatory standards and ensure patient safety before the clinical deployment of mito-lncRNA therapeutics for cardiovascular disease [77].

Clinical translation of mito-lncRNAs: challenges and opportunities

Mito-lncRNAs have moved beyond basic mechanistic studies into early-phase clinical evaluation, particularly in cardiovascular disease. Several mito-lncRNAs, including LIPCAR, RMRP, H19, and MALAT1, already show promising biomarker potential, yet each illustrates both the promise and the pitfalls of translating non-coding RNA biology into real-world diagnostics and therapy. Building on findings from other lncRNA families, this section examines how these mito-lncRNAs fit into the larger framework of clinical translation—first as biomarkers, then as therapeutic targets, and finally as vehicles for precision cardiology (Fig. 5).

Fig. 5. Clinical translation pathways of mito-lncRNAs in cardiovascular disease: biomarkers, therapeutic challenges, and precision cardiology opportunities.

a Clinical translation as biomarkers. Circulating mito-lncRNAs—including LIPCAR, RMRP, H19, and MALAT1—are detectable in plasma or serum, often stabilized within exosomes or extracellular vesicles. These transcripts reflect mitochondrial and vascular stress in conditions such as heart failure, myocardial infarction, and CAD. Quantification using qRT-PCR or droplet digital PCR (ddPCR) enables non-invasive assessment of diagnosis, prognosis, and risk stratification. However, technical standardization challenges—including normalization strategies, inter-laboratory variability, and the need for large prospective multiethnic cohorts—must be addressed before routine clinical implementation. b Therapeutic translation and associated challenges. Advancing mito-lncRNAs as therapeutic targets requires rigorous validation through gain- and loss-of-function studies in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, as well as in vivo disease models. Delivery platforms under investigation include cardiotropic adeno-associated virus (AAV) vectors, lipid nanoparticles (LNPs), and antisense oligonucleotides (ASOs). Major translational barriers include efficient cardiac and mitochondrial-specific delivery, off-target RNA interactions, immune activation, long-term systemic effects, and limited cross-species sequence conservation. c Opportunities in precision cardiology. Mito-lncRNAs signatures may enable refined phenotyping of cardiovascular disease based on mitochondrial pathobiology (e.g., energy-deficient versus fibrotic phenotypes). Integration of mito-lncRNAs biomarkers with mitochondria-targeted pharmacologic agents—such as ROS scavengers or electron transport chain modulators—may permit synergistic therapeutic strategies. Together, these approaches support the development of mitochondria-centered precision diagnostics and targeted interventions in cardiovascular medicine.

Clinical translation as biomarkers

Among the best-characterized mito-lncRNAs, LIPCAR has emerged as a repeatedly validated circulating biomarker of cardiac remodeling and heart failure progression, including in patients with reduced ejection fraction and in post-myocardial-infarction myocardium [60, 61]. LIPCAR is stably detectable in plasma and serum, likely protected by association with exosomes or other extracellular vesicles. Its levels are independent of conventional risk factors after appropriate normalization to reference RNAs such as GAPDH or U6 snRNA [60]. In prospective cohort studies, rising LIPCAR levels are associated with deterioration of left ventricular remodeling and can predict adverse outcomes, such as all-cause mortality and hospitalization. This positions LIPCAR as a noninvasive indicator of mitochondrial health that reflects myocardial energetic stress [60].

Parallel data highlight RMRP as a circulating marker of CAD severity: serum RMRP levels are significantly elevated in CAD patients and strongly correlate with the SYNTAX score, suggesting that RMRP reflects the burden of obstructive lesions [54, 55]. In addition, high RMRP expression is associated with a greater risk of MACEs, and receiver-operating characteristic analysis yields robust AUCs above 0.85, underscoring its diagnostic and prognostic utility [37]. Similarly, H19 and MALAT1—though not strictly mitochondrial—have repeatedly been linked to atherosclerotic burden, myocardial infarction risk, and heart failure phenotypes. Multiple meta-analyses report that elevated plasma or tissue levels of H19 and MALAT1 appreciably increase CAD risk and predict disease severity [70, 88]. These findings collectively support a role for lncRNAs, including mito-lncRNAs, as non-invasive signatures of mitochondrial and vascular stress.

From a technical standpoint, most mito-lncRNAs biomarker work relies on RT-qPCR and emerging droplet-digital PCR platforms, which offer high sensitivity and dynamic range for low-abundance circulating transcripts [88]. However, standardization remains a major hurdle: pre-analytical variables (e.g., sample collection time, fasting status, anticoagulant used), normalization strategies (which “housekeeping” lncRNA or miRNA to select), and inter-laboratory assay differences all contribute to variability [85, 89]. Current studies also suffer from modest cohort sizes, predominantly single-center designs, and limited ethnic diversity, limiting generalizability. To move toward routine use, mito-lncRNA biomarkers will need large, multi-ethnic, prospective validation cohorts, centralized assay harmonization, and clearly defined cutoff values for diagnosis and risk stratification [89].

Therapeutic translation

Before any mito-lncRNAs become bona fide therapeutic targets, rigorous target validation is required, including loss- and gain-of-function experiments in relevant cell types (cardiomyocytes, endothelial cells, vascular smooth muscle) and in vivo models of ischemia, hypertrophy, and heart failure [40]. For example, RMRP, GAS5, and MALAT1 have been shown to regulate fibrosis, hypertrophy, and vascular remodeling, suggesting that modulating their activity could influence myocardial energetics and electrical stability [38, 43, 63]. Yet most of these data come from overexpression or knockdown studies in cell culture or from local tissue delivery, and systemic, long-term effects on mitochondrial homeostasis remain incompletely characterized.

A key challenge is achieving mitochondrial-specific delivery. To effectively engage mito-lncRNAs, vectors must reach the mitochondrial-rich myocardium and ideally localize within or near mitochondria themselves [16, 19]. Current modalities under investigation include adeno-associated virus (AAV) serotypes with cardiac tropism, lipid nanoparticles (LNP) engineered for myocardial uptake, and antisense oligonucleotides (ASOs) designed to modulate RNA–RNA interactions or splicing [16, 80]. However, each approach carries risks: off-target RNA binding, immune activation by synthetic nucleic acid-based therapeutics, and potential cross-species discordance in lncRNA sequence and function can all confound translational success [88]. For example, some lncRNAs show only limited sequence conservation, making it difficult to extrapolate mouse-model phenotypes directly to humans and raising safety concerns about disrupting non-mitochondrial functions of the same transcript.

Opportunities

Despite these hurdles, there are significant clinical opportunities related to mito-lncRNAs. First, circulating mito-lncRNAs are inherently noninvasive. They can be measured repeatedly through blood tests. This enables ongoing monitoring of mitochondrial health, treatment response, and risk classification, all without the need for repeated imaging or invasive procedures [85]. Second, because many mito-lncRNAs, such as LIPCAR, RMRP, and GAS5, act within or near mitochondria, targeting them may confer a degree of tissue specificity. This reduces systemic toxicity compared with broad-spectrum mitochondrial modulators, which often affect all high-energy-demand organs indiscriminately [16, 37, 39, 90].

In precision cardiology, mito-lncRNA signatures could complement conventional biomarkers by distinguishing phenotypes that appear similar clinically but have different mitochondrial pathobiology. For example, they can distinguish “high-energy-deficient” heart failure from “high-fibrotic” heart failure. They can also identify patients whose CAD is more driven by endothelial dysfunction rather than VSMC proliferation [91]. Moreover, mito-lncRNAs could be rationally combined with mitochondria-targeted drugs (e.g., mito-ROS scavengers, electron-transport-chain modulators, or mitophagy regulators) to generate synergistic therapeutic regimens that tune mitochondrial behavior rather than simply suppressing downstream symptoms [87, 92].

In summary, LIPCAR, RMRP, H19, and MALAT1 illustrate how mitochondrial and lncRNA biology can be harnessed for cardiovascular diagnostics while underscoring the need for standardized biomarker workflows, rigorous target validation, and mitochondria-tailored delivery systems. By addressing these challenges, the translational pipeline for mitochondrial lncRNAs has the potential to move from mechanistic curiosity toward real-world tools for risk prediction, diagnosis, and targeted therapy in cardiovascular medicine.

Conclusion and future perspectives

Mito-lncRNAs have emerged as key regulators of cardiac mitochondrial homeostasis, influencing bioenergetics, oxidative stress responses, calcium handling, and mitochondrial quality control. Dysregulation of molecules such as LIPCAR, MALAT1, RMRP, H19, and lncND5 has been linked to AMI, heart failure, cardiomyopathy, and pulmonary hypertension [37, 41, 55, 88, 90]. Several of these transcripts demonstrate promising diagnostic and prognostic performance in early clinical studies. Preclinical models further suggest that correcting disease-associated mitochondrial lncRNA imbalances can partially restore mitochondrial function and attenuate cardiac dysfunction. Together, these findings position mito-lncRNAs as mechanistically informative candidates for biomarker development and, potentially, therapeutic modulation.

However, the field remains in an early translational stage, and key challenges must be addressed systematically. Methodological limitations in defining true mitochondrial localization, an incomplete understanding of compartment-specific mechanisms, limited sequence conservation across species, and inefficient delivery to the heart and mitochondria remain major barriers. To address these challenges, future work should explicitly link each challenge to targeted experimental strategies. Detection and localization issues will require orthogonal validation, including rigorously controlled mitochondrial fractionation, high-resolution RNA imaging, and emerging single-cell and spatial transcriptomic approaches. These methods help distinguish genuine mitochondrial signals from nuclear or cytoplasmic ones. Mechanistic ambiguity should be addressed with compartment-restricted gene-editing or silencing tools, RNA–protein interactome mapping, and structure–function analyses to identify the domains and interactions that drive mitochondrial phenotypes. To improve translational relevance, greater emphasis should be placed on human iPSC-derived cardiomyocytes, engineered cardiac tissues, organoids, and humanized or large-animal models that better capture human-specific lncRNA regulation. On the therapeutic front, progress will depend on developing cardiotropic and mitochondria-directed RNA delivery platforms—such as optimized viral vectors, lipid-based systems, or RNA constructs incorporating targeting motifs—alongside standardized frameworks for assessing biodistribution, immunogenicity, and long-term safety. For biomarker translation, large, multicenter, and ethnically diverse prospective studies with harmonized assay protocols will be essential to determine whether mito-lncRNA signatures provide robust, incremental value over existing clinical tools. If these methodological and translational challenges are addressed in a coordinated manner, mito-lncRNAs have the potential to contribute meaningfully to more precise risk stratification and to targeted modulation of mitochondrial dysfunction in cardiovascular disease.

Author contributions

AIC, NX, ZFH, and BSM conceived, designed, and wrote the review article; FC, YTL, YFL, and WHD checked and supplemented the contents of the figures and tables; JYH, ZYH, and ZT checked for spelling errors and revised grammatical errors; CS and  HBL reviewed and revised the manuscript.

Competing interests

The authors declare no competing interests.

Generative AI statement

The author(s) declare that Generative AI was used in the creation of this manuscript. Generative AI was used solely for grammar and language editing during manuscript preparation.