Mitochondrial Dysfunction in Type 2 Diabetes and Metabolic Syndrome: Mechanisms, Biomarkers, and Emerging Therapies

Abstract

Background

Mitochondrial dysfunction is increasingly recognized as a bidirectional component of type 2 diabetes (T2D) and metabolic syndrome, linking nutrient excess, lipotoxicity, oxidative stress, inflammation, impaired insulin signaling, and pancreatic β-cell failure. However, its causal position and clinical actionability remain uncertain because mitochondrial abnormalities vary by tissue, disease stage, and metabolic phenotype.

Objective

To critically synthesize mechanistic, biomarker, imaging, and therapeutic evidence concerning mitochondrial dysfunction in T2D and metabolic syndrome, with emphasis on evidence maturity and clinical translation.

Methods

We conducted a structured narrative review of preclinical, translational, and clinical literature published primarily from 2015 through 2025. The search intentionally included established glucose-lowering therapies and selected mitochondria-directed agents and was not intended to be exhaustive. Because this was not a systematic review, no PRISMA flow diagram, formal risk-of-bias assessment, or standardized evidence grading was performed.

Results

Mitochondrial abnormalities in T2D include impaired oxidative phosphorylation, excessive reactive oxygen species, altered fission-fusion and mitophagy, disrupted calcium handling, metabolic inflexibility, and β-cell bioenergetic failure. The evidence supports a bidirectional model in which inherited susceptibility, aging, nutrient overload, visceral adiposity, lipotoxicity, and inflammation can impair mitochondria, while mitochondrial stress further amplifies insulin resistance and organ dysfunction. Candidate biomarkers and imaging methods remain predominantly research tools because specificity, assay standardization, validated thresholds, and prospective clinical utility are limited. Exercise, weight reduction, GLP-1 receptor agonists, and SGLT2 inhibitors have established clinical benefits and may improve mitochondrial biology indirectly or directly; in contrast, NAD⁺ precursors, targeted antioxidants, mitophagy enhancers, and other dedicated mitochondrial modulators remain investigational, with target engagement generally exceeding demonstrated glycemic benefit.

Conclusion

Mitochondrial dysfunction is best understood as a context-dependent driver, consequence, and amplifier of metabolic disease rather than a universal single cause. Translation will require standardized biomarker panels, noninvasive phenotyping, adequately powered randomized trials with longer follow-up, and prospective identification of patients whose mitochondrial phenotype is likely to be treatment-responsive.

Introduction

Type 2 diabetes (T2D) and metabolic syndrome are major and overlapping global health problems. The International Diabetes Federation estimated that 589 million adults aged 20–79 years were living with diabetes in 2024 and projected that this number will reach 853 million by 2050.¹ Metabolic syndrome is diagnosed when a specified combination of central adiposity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose is present; insulin resistance is central to its pathophysiology but is not itself a mandatory diagnostic criterion.^2–4 These conditions substantially increase the risks of cardiovascular, renal, hepatic, and other metabolic complications.

Mitochondria integrate nutrient oxidation, ATP production, redox signaling, calcium homeostasis, organelle quality control, and stress responses. In skeletal muscle, liver, adipose tissue, and pancreatic β-cells, chronic nutrient excess can exceed oxidative demand and promote incomplete fatty-acid oxidation, toxic lipid intermediates, reactive oxygen species (ROS), and inflammatory signaling.^5–10 Conversely, established insulin resistance, hyperglycemia, lipotoxicity, inflammation, and aging can themselves impair mitochondrial content, respiratory function, dynamics, and mitophagy. Rare primary mitochondrial disorders can produce diabetes-like phenotypes with early β-cell failure, but common T2D is heterogeneous and cannot be explained by a single mitochondrial defect.⁸

Recent reviews have often focused separately on molecular mechanisms, individual biomarker classes, or selected therapeutic compounds. The added contribution of this review is an integrated and explicitly translational synthesis that connects tissue-specific mechanisms with biomarker and imaging readiness, distinguishes established therapies from investigational mitochondrial agents, compares supportive and conflicting evidence, and examines why promising preclinical findings have produced limited clinical benefit. We therefore address four linked questions: how mitochondrial dysfunction participates in T2D and metabolic syndrome; whether it is a cause, consequence, or bidirectional amplifier; which biomarkers are closest to clinical use; and which therapeutic strategies have evidence sufficient to influence current or future practice.

Materials and Methods

Search Strategy

We conducted a structured narrative literature search using PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov, focusing primarily on literature published from 2015 through 2025 while retaining selected earlier seminal studies needed for mechanistic context. Search concepts included mitochondrial dysfunction, type 2 diabetes, metabolic syndrome, bioenergetics, insulin resistance, β-cell function, oxidative phosphorylation, lipotoxicity, calcium signaling, mitochondrial dynamics, mitophagy, biomarkers, imaging, GLP-1 receptor agonists, SGLT2 inhibitors, NAD⁺ precursors, mitochondria-targeted antioxidants, elamipretide, urolithin A, spermidine, imeglimin, and mitochondrial pyruvate-carrier modulators. The searches combined disease-related terms with mitochondrial, mechanistic, biomarker, imaging, and therapeutic concepts using database-appropriate Boolean combinations. Because this work was designed as a narrative review rather than a systematic review, complete database-specific historical search strings, record-level search logs, and screening counts were not prospectively retained. The search was structured to support a narrative synthesis and was not intended to be exhaustive or reproducible at the level expected for a systematic review. The inclusion of selected named therapeutic compounds was an intentional scoping decision intended to capture prominent translational candidates; however, this approach may have preferentially retrieved studies involving those agents and underrepresented competing interventions, neutral or negative findings, or therapies indexed under different terminology. Treatment-related conclusions were therefore interpreted cautiously and in the context of the broader clinical evidence base.

Inclusion and Exclusion Criteria

Eligible evidence included primary preclinical studies, human mechanistic and observational studies, randomized and nonrandomized clinical trials, systematic reviews, and meta-analyses relevant to mitochondrial mechanisms, biomarkers, imaging, or therapeutic interventions in type 2 diabetes or metabolic syndrome. Human clinical evidence was prioritized when available. Case reports and very small uncontrolled series without broadly informative mechanistic or translational relevance were generally excluded. Evidence types were not treated as equivalent. Mechanistic and preclinical studies were used primarily to explain biological plausibility and pathways, whereas observational human studies were used to characterize associations and translational relevance. Randomized clinical trials were given greater weight when evaluating treatment efficacy and clinical applicability, and systematic reviews and meta-analyses were used to contextualize the consistency and overall direction of clinical evidence. Mechanistic findings alone were not considered sufficient to establish clinical causality or therapeutic efficacy.

Study Selection and Data Extraction

Two authors independently screened potentially relevant titles and abstracts and extracted information regarding the study population or experimental model, tissue examined, mitochondrial measurement, metabolic outcome, intervention, comparator, and stage of clinical development. Disagreements were resolved through discussion. Because the review was not prospectively conducted as a systematic review, record-level search yields, duplicate counts, numbers screened, and reasons for exclusion were not formally documented in a PRISMA-style study-flow process and therefore cannot be reported retrospectively with sufficient accuracy. We have explicitly identified this as a limitation rather than reconstructing screening numbers after completion of the review.

Synthesis Approach

Evidence was synthesized thematically across molecular, cellular, organ, and clinical levels. We explicitly distinguished preclinical findings, human mechanistic studies, observational evidence, randomized clinical trials, systematic reviews, and meta-analyses according to their evidentiary role. Preclinical findings were interpreted as providing mechanistic plausibility rather than direct evidence of clinical causality. Human observational studies were interpreted primarily as evidence of association, while randomized clinical trials were given greater weight for claims regarding therapeutic efficacy. Convergence and disagreement across evidence types were considered separately, particularly regarding whether mitochondrial dysfunction represents a cause, consequence, or amplifier of insulin resistance and metabolic disease. We also distinguished biochemical or molecular target engagement from clinically meaningful outcomes such as glycemic control, cardiometabolic events, and treatment response. These procedures provide a structured and transparent framework for narrative synthesis but do not confer the completeness, reproducibility, prospective protocol specification, formal risk-of-bias assessment, or certainty grading expected of a systematic review.

Review

Mitochondrial Bioenergetics and Glucose Homeostasis

Mitochondria are central hubs of energy metabolism that tightly orchestrate how the body uses carbohydrates and lipids, thereby maintaining glucose homeostasis.

ATP Generation and Fuel Oxidation

Mitochondria oxidize pyruvate derived from glucose and fatty acids to generate ATP through the tricarboxylic acid cycle and electron transport chain. In skeletal muscle and liver, the relative use of carbohydrate and lipid fuels changes with nutrient availability, hormonal signaling, and energy demand. Fatty-acid β-oxidation supplies acetyl-CoA and reducing equivalents for oxidative phosphorylation, whereas controlled mitochondrial reactive oxygen species (ROS) participate in physiological redox signaling. When respiratory flux, substrate delivery, or antioxidant capacity becomes imbalanced, ATP production and redox homeostasis can deteriorate and impair insulin action.^5,11,12

Fed vs Fasting Adaptations

In healthy individuals, mitochondrial function dynamically adapts between feeding and fasting states. After feeding (high glucose and insulin), mitochondria in muscle preferentially oxidize glucose while excess energy is stored; in contrast, during fasting or exercise, a low-insulin/high-glucagon milieu shifts metabolism toward fat oxidation. Key molecular sensors tune these transitions. AMP-activated protein kinase (AMPK) is activated by low energy (high AMP) during fasting/exercise and promotes catabolic processes — it enhances mitochondrial fat oxidation and even drives mitochondrial biogenesis via downstream targets like PGC-1α. On the other hand, mTOR kinase responds to feeding by promoting anabolic processes and can downregulate autophagy and mitochondrial turnover when nutrients are abundant. The PGC-1α coactivator is often called a “master regulator” of mitochondrial biogenesis and function, integrating signals from AMPK, sirtuins (SIRT1/3), and others.¹² During fasting or exercise, PGC-1α levels rise and induce transcription of genes for oxidative enzymes and mitochondrial proteins, effectively boosting the mitochondrial oxidative capacity to meet increased energy demand. Sirtuin 1 (SIRT1), which senses the NAD⁺/NADH ratio, also activates PGC-1α by deacetylation, linking the cell’s redox state to mitochondrial adaptation.¹² Through such pathways, mitochondria in a healthy state remain metabolically flexible — able to switch between fuels and ramp up ATP production or heat generation (via uncoupling proteins) appropriate to the physiological state. This metabolic flexibility is fundamental to maintaining glucose homeostasis: when glucose is plentiful, mitochondria help dispose of it; when glucose is scarce, mitochondria sustain tissues by oxidizing fats and preserving blood glucose for critical needs.

Cross-Talk with Insulin Signaling

Insulin signaling and mitochondrial metabolism interact bidirectionally. In skeletal muscle, insulin promotes glucose uptake and coordinates pyruvate oxidation with ATP demand. When mitochondrial oxidative capacity is inadequate relative to substrate delivery, glucose and fatty acids are incompletely oxidized, cellular energy stress increases, and lipid intermediates accumulate. Chronic nutrient and insulin exposure can further impair oxidative phosphorylation and mitochondrial turnover. Conversely, mitochondrial ROS and lipid-derived signals can activate stress kinases that disrupt insulin-receptor substrate signaling. Physiological ROS participate in signaling, whereas sustained ROS excess impairs insulin action. AMPK, SIRT1, and PGC-1α link cellular energy status to mitochondrial biogenesis and insulin sensitivity, helping explain why exercise can improve both mitochondrial capacity and insulin responsiveness. These observations support reciprocal reinforcement rather than a simple one-directional pathway.

Mechanistic Insights into Mitochondrial Dysfunction in T2D

Mitochondrial abnormalities in various tissues can contribute to pathological changes associated with T2D and metabolic syndrome. Here we summarize key mechanisms by which mitochondrial function becomes altered and how these changes may contribute to insulin resistance, hyperglycemia, and β-cell failure.

Oxidative Phosphorylation Defects

Electron Transport Chain (ETC) Impairment

Reduced oxidative phosphorylation has been reported in skeletal muscle and other tissues in T2D, although the magnitude and causal meaning vary among studies. One frequently cited study reported an approximately 40% reduction in NADH oxidoreductase activity measured polarographically, reflecting predominantly complex I-linked respiration, rather than a nonstandard “P(33)” enzyme.¹³ Lower activities of complexes II and IV have also been described. However, mitochondrial abnormalities are neither uniform nor necessarily primary: liver mitochondria may maintain or increase fatty-acid oxidation during early insulin resistance, and some defects normalize after controlling for physical activity, adiposity, or substrate availability. Thus, reduced respiratory capacity may predispose to metabolic inflexibility in some individuals, while in others it develops secondarily after chronic glucolipotoxic stress.

Skeletal muscle often exhibits prominent reductions in oxidative capacity in T2D, whereas hepatic mitochondrial responses may be less pronounced or may include compensatory increases in fatty-acid oxidation during insulin resistance. Pancreatic β-cell responses also appear to vary with disease stage and metabolic stress. Early chronic glucose exposure can increase mitochondrial respiration and resting ATP/ADP as an adaptive response, whereas established T2D is associated with impaired glucose-responsive mitochondrial metabolism and defective stimulus-secretion coupling.^8,14 Together, these findings indicate that abnormalities in mitochondrial respiratory capacity occur in several tissues in T2D, but their magnitude, direction, and functional consequences vary according to tissue, disease stage, metabolic phenotype, and experimental context. Reduced oxidative capacity in skeletal muscle may contribute to peripheral insulin resistance, whereas β-cell mitochondrial impairment may contribute to defective stimulus-secretion coupling and progressive secretory failure.

Mitochondrial Content and Biogenesis

Reduced mitochondrial content or biogenesis has been reported in some insulin-responsive tissues. Skeletal muscle from insulin-resistant individuals may contain fewer or smaller mitochondria and show lower expression of mitochondrial biogenesis regulators such as PGC-1α and nuclear respiratory factors (NRF-1/2).⁵ However, mitochondrial quantity alone does not explain T2D. Some evidence suggests that intrinsic respiratory function per mitochondrion may also be reduced in T2D skeletal muscle.⁵ Acquired mtDNA damage associated with aging or chronic metabolic stress may further impair mitochondrial performance. Interventions such as exercise can promote mitochondrial biogenesis and improve insulin sensitivity, supporting the importance of both mitochondrial quantity and quality in metabolic health.⁵

Tissue-Specific Variations

In skeletal muscle, mitochondrial abnormalities may manifest as reduced oxidative capacity and altered lipid oxidation and are associated with insulin resistance severity. Hepatic mitochondrial responses are more heterogeneous and may include preserved or increased oxidative activity in some stages of insulin resistance. Pancreatic β-cells can initially mount compensatory increases in mitochondrial metabolism during chronic glucose exposure, but prolonged glucolipotoxic stress may ultimately impair mitochondrial function and glucose-stimulated insulin secretion.^8,14 These tissue-specific patterns support a context-dependent contribution of mitochondrial dysfunction rather than a uniform defect across organs.

Oxidative Stress and ROS Overproduction

Mitochondrial ROS and Insulin Resistance

Nutrient overload in obesity and T2D increases electron pressure within the electron transport chain (ETC), promoting mitochondrial reactive oxygen species (ROS) formation. Chronically elevated ROS can activate stress kinases, impair insulin-receptor signaling, promote inflammatory gene expression, and damage mitochondrial DNA and proteins, thereby creating a self-reinforcing cycle of respiratory dysfunction.^5,15 A 2025 study by Goncalves et al identified hepatic coenzyme Q deficiency and reverse electron transport at complex I as a specific source of excess mitochondrial ROS in obesity.¹¹ Restoring coenzyme Q balance reduced ROS and improved metabolic homeostasis in experimental models. These findings illustrate the importance of identifying the source and context of ROS rather than assuming that nonspecific antioxidant treatment will be effective; clinical results with antioxidant strategies have remained mixed.

ROS in β-Cell Glucotoxicity/Lipotoxicity

Pancreatic β-cells are exquisitely sensitive to oxidative stress. They have relatively low expression of antioxidant enzymes, meaning ROS readily accumulate under stress. Chronic hyperglycemia (glucotoxicity) and elevated fatty acids (lipotoxicity) drive β-cells to overproduce mitochondrial ROS, which in turn triggers pathways of apoptosis or dedifferentiation. Excess ROS can damage mitochondrial membranes and activate intrinsic apoptotic signals in β-cells, contributing to their progressive loss in T2D. Evidence of oxidative damage is seen in human islets from diabetic donors — for instance, higher levels of lipid peroxidation byproducts have been found in T2D islets, indicating ROS attack on membranes.¹⁶ These lipid peroxides further impair mitochondrial function, creating a downward spiral of β-cell stress.¹⁶ ROS also disrupts the normal signaling role of mitochondria in insulin secretion; an overload of ROS may prevent the mitochondrial metabolic signals (ATP, NADH, etc) from properly triggering insulin granule exocytosis. In addition, ROS can induce endoplasmic reticulum (ER) stress in β-cells by disturbing the delicate ER–mitochondria Ca²⁺ balance. The end result of chronic oxidative stress is often β-cell apoptosis or dysfunction, contributing to the decline in insulin levels in long-standing T2D. Antioxidants have been shown to protect β-cells in rodent models — for example, overexpressing catalase in β-cells preserves insulin secretion under diabetic diets. However, translating this clinically is challenging. Overall, oxidative stress forms a common link between nutrient-induced mitochondrial strain and the cellular dysfunction of both insulin-resistant tissues and β-cells in T2D. Controlling ROS production at its mitochondrial source remains a key goal to break this link.

Mitochondrial Quality Control Failure

Mitochondria continually undergo fission (splitting) and fusion (joining) to maintain a healthy network and eliminate damaged segments — processes collectively termed mitochondrial dynamics. In addition, damaged mitochondria are removed by a specialized autophagy process called mitophagy. In T2D and metabolic syndrome, there is often an imbalance in these quality control mechanisms.

Dysregulated Fission/Fusion

Nutrient excess and oxidative stress can shift mitochondrial dynamics toward excessive fission and network fragmentation. High-fat feeding and obesity can activate the fission mediator DRP1, whereas the fusion proteins MFN1, MFN2, and OPA1 may be reduced in insulin-resistant tissues.¹⁷ A fragmented network can impair content exchange, respiratory efficiency, quality control, and communication with the endoplasmic reticulum. Experimental evidence also links altered fission-fusion balance in adipose tissue with systemic insulin sensitivity.¹⁸ These findings support mitochondrial dynamics as a contributor to metabolic dysfunction, although the direction and magnitude of the effect vary by tissue and disease model.

Defective Mitophagy

Mitophagy is essential for removing damaged mitochondria and maintaining organelle quality. The PINK1-Parkin pathway is a major mechanism for identifying damaged mitochondria and targeting them for autophagic degradation. Disturbances of mitophagy have been reported across experimental models of diabetes and its complications.¹⁹ For example, high glucose suppressed PINK1/Parkin-mediated mitophagy and promoted apoptosis in a neuronal cell model relevant to diabetic neuropathy.²⁰ Such findings support a role for defective mitochondrial quality control under hyperglycemic stress, although the magnitude and direction of mitophagy abnormalities vary by tissue and experimental context. Experimental studies have also explored agents such as urolithin A and spermidine as potential modulators of mitochondrial quality control, but clinical evidence in T2D remains limited. Overall, impaired mitophagy may contribute to mitochondrial stress in diabetes, but it should not be interpreted as a uniform or independently established cause across all tissues.

An integrated schematic of these interconnected mitochondrial defects in T2D is presented in Figure 1.

Figure 1.

Integrated multiple-hit model of mitochondrial dysfunction in type 2 diabetes and metabolic syndrome. Hyperglycemia, nutrient overload, chronic inflammation, visceral adiposity, and excess free fatty acids converge on impaired oxidative phosphorylation, excessive mitochondrial ROS, mitochondrial DNA damage, disturbed calcium handling, altered fission-fusion, and impaired mitophagy. These abnormalities promote metabolic inflexibility, impaired insulin signaling, β-cell stress and apoptosis, and cardiometabolic organ injury, while metabolic disease feeds back to intensify upstream stressors. Arrows indicate proposed directional or reinforcing relationships rather than universal causality. Original figure created by the authors. Red upward arrows indicate increased activity or expression; red downward arrows indicate decreased activity or expression; red X symbols indicate inhibition or dysfunction; dashed arrows indicate indirect or proposed mechanistic relationships; double-headed arrows indicate bidirectional interactions or feedback mechanisms.

Abbreviations: ATP, adenosine triphosphate; Ca2+, calcium ion; ETC, electron transport chain; FFA, free fatty acids; mtDNA, mitochondrial DNA; NF-kB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; ROS, reactive oxygen species.

Altered Substrate Utilization

Metabolic health depends on mitochondria appropriately switching between substrates (glucose vs fatty acids) and fully oxidizing them. In T2D, this metabolic flexibility is impaired.

Fuel Preference Shifts

Skeletal muscle in insulin resistance often becomes biased toward fat oxidation even in the fed state, due to an inability to efficiently uptake and oxidize glucose. This leads to chronically elevated fat burning and accumulation of unused glucose, contributing to hyperglycemia. Paradoxically, when faced with an acute lipid load (after a high-fat meal), insulin-resistant muscle fails to further increase fat oxidation — a phenomenon known as metabolic inflexibility.²¹ Due to the inability of mitochondria to increase beta-oxidation to any great extent, excess fatty acids are diverted to either being stored or producing toxic intermediates. Consequently, in T2D muscle, glucose oxidation is reduced even though it would normally occur, and the oxidation of fat is either not restricted as it should be or increased to the degree that is required. The inability of muscle tissue to match the requirements of energy consumption and production further increases the energy surplus within the muscle tissue and promotes insulin resistance.

Impaired substrate switching can be accompanied by accumulation of intermediates associated with incomplete oxidation. Medium- and long-chain acylcarnitines are often elevated in obesity and insulin resistance and have been investigated as indirect markers of altered fatty-acid handling and metabolic inflexibility.²² However, circulating acylcarnitines are not specific measures of mitochondrial dysfunction and may reflect fatty-acid supply, β-oxidation flux, tissue export, and the broader systemic metabolic state. Lactate concentrations are also associated with insulin resistance and incident T2D, but lactate is influenced by multiple physiological and pathological factors and should not be interpreted as a direct measure of mitochondrial oxidative capacity.²³ These findings therefore support altered systemic substrate handling in T2D rather than a uniform limitation of mitochondrial oxidative capacity.

Visceral adiposity adds an important lipid and calcium-signaling dimension to this model. Increased delivery of nonesterified fatty acids to liver, muscle, myocardium, and β-cells promotes diacylglycerol and ceramide accumulation, oxidative pressure, and altered endoplasmic-reticulum-mitochondrial contact sites. Disturbed calcium transfer can either deprive mitochondria of the calcium signals needed to match ATP production to demand or produce calcium overload, permeability-transition pore opening, ROS generation, and cell injury. This interaction links lipotoxicity with insulin resistance, β-cell dysfunction, and cardiovascular complications, as summarized in the integrative framework in Figure 1.

Toxic Lipid Intermediates

Inefficient mitochondrial fat handling also contributes to the accumulation of lipid-derived signaling molecules that cause insulin resistance. Notably, diacylglycerols (DAGs) and ceramides build up in insulin target tissues when mitochondrial fat oxidation lags behind supply. DAGs activate novel protein kinase C (PKC) isoforms (ε in liver, θ in muscle) which phosphorylate and inhibit insulin receptor kinase activity, producing insulin resistance at the cellular level.²⁴ Ceramides, on the other hand, can induce insulin resistance by blocking Akt/PKB activation and promoting inflammatory pathways. Mitochondrial dysfunction contributes to this because normally a significant portion of fatty acids would be oxidized rather than shunted into DAG/ceramide synthesis. For example, overexpression of mitochondrial fatty acid oxidation enzymes in muscle has been shown to reduce DAG content and improve insulin signaling, whereas impairment of mitochondrial fat import leads to DAG accumulation and insulin resistance. There is also evidence that ceramides may directly impair mitochondria by promoting fission and ROS production, creating a deleterious loop. In summary, a hallmark of T2D at the tissue level is fuel inflexibility — an inability of mitochondria to appropriately utilize and switch fuels — leading to both energy dysregulation and the accumulation of “lipotoxic” intermediates that degrade insulin signaling.²¹ Addressing this issue might involve interventions that restore metabolic flexibility (exercise, which reconditions muscle to oxidize fuels efficiently, or agents that mimic fasting signals to spur mitochondrial fat use).

β-Cell Mitochondrial Dysfunction

Pancreatic β-cells rely on mitochondria as metabolic sensors that trigger insulin secretion. In health, a rise in blood glucose leads to increased glucose uptake and metabolism in β-cells, raising the ATP/ADP ratio, which closes K_ATP channels and depolarizes the cell, culminating in Ca²⁺ influx and insulin exocytosis. Mitochondria are at the heart of this process — they supply the ATP and also other coupling factors (like glutamate, NADPH, and perhaps short-chain acyl-CoAs) that amplify insulin release. In T2D, this finely tuned mechanism is disrupted by mitochondrial dysfunction in β-cells.

Impaired ATP Generation and Insulin Secretion

Pancreatic β-cell mitochondria are central to glucose-stimulated insulin secretion because mitochondrial metabolism helps generate the ATP and metabolic coupling signals required for insulin exocytosis. Studies of human pancreatic islets indicate that mitochondrial adaptation varies with the stage and duration of metabolic stress. Early chronic glucose exposure can increase mitochondrial respiration and resting ATP/ADP levels as an adaptive response, whereas islets from individuals with established T2D have been reported to exhibit impaired glucose-responsive mitochondrial metabolism and defective stimulus-secretion coupling.^8,14 Genetic forms of diabetes caused by primary mitochondrial defects further demonstrate the importance of β-cell mitochondrial function; for example, maternally inherited diabetes and deafness is associated with pathogenic mtDNA variants and β-cell failure.⁸ These observations demonstrate that severe primary mitochondrial defects can be sufficient to produce diabetes in specific mitochondrial syndromes, while in common T2D, β-cell mitochondrial dysfunction is better interpreted as one contributing mechanism among multiple interacting genetic, metabolic, and environmental factors.

Mitochondria-ER Crosstalk and β-Cell Stress

Beyond ATP supply, pancreatic β-cell mitochondria communicate closely with the endoplasmic reticulum (ER) at mitochondria-associated membranes to coordinate calcium flux, metabolic amplification, and insulin secretion. Calcium entering through voltage-gated channels stimulates mitochondrial metabolism and ATP production, thereby supporting glucose-stimulated insulin secretion.¹⁶ Chronic glucolipotoxicity, ER stress, and inflammatory cytokine signaling can disturb ER-mitochondrial coupling. JNK-dependent changes in calcium transfer may produce inadequate mitochondrial calcium signaling or calcium overload; overload can promote permeability-transition pore opening and apoptosis, whereas insufficient transfer can blunt metabolic amplification.²⁵ ER stress and mitochondrial ROS can reinforce one another, contributing to β-cell dysfunction, dedifferentiation, and loss. These mechanisms provide a rationale for preserving organelle communication and mitochondrial quality, but direct clinical evidence for mitochondria-specific β-cell therapies remains limited.

Clinical Biomarkers and Imaging of Mitochondrial Dysfunction

Translating mitochondrial dysfunction into the clinic requires tools to measure it in patients. Several circulating biomarkers and noninvasive imaging techniques are under investigation to assess mitochondrial health in metabolic diseases.

Circulating Metabolite Biomarkers

Circulating metabolites can provide indirect information about systemic metabolic stress and substrate handling but generally lack specificity for mitochondrial dysfunction. Lactate may increase when glycolytic flux exceeds oxidative disposal, but its concentration is also influenced by exercise, tissue perfusion, hepatic clearance, medications, and other physiological or pathological factors. Higher plasma lactate has been associated with incident T2D in prospective studies.²³ Similarly, abnormal acylcarnitine profiles may accompany incomplete fatty-acid oxidation and metabolic inflexibility, but they should be interpreted as associative metabolic signatures rather than direct or specific measurements of mitochondrial dysfunction.^26,27 Other candidate signals, including ketone bodies, branched-chain amino-acid-related metabolites, and FGF21, may reflect broader metabolic or cellular stress. FGF21 in particular is influenced by multiple tissues and conditions and should not be interpreted as a mitochondria-specific biomarker.

Cell-Free Mitochondrial DNA (cf-mtDNA)

Mitochondrial DNA fragments can be released into the circulation during cellular stress or injury. Circulating cell-free mitochondrial DNA (cf-mtDNA) is being investigated as a nonspecific marker of cellular and mitochondrial stress, tissue injury, and inflammatory signaling rather than as a direct measure of mitochondrial function. Altered circulating mtDNA measures have been reported in cardiometabolic populations, including people with diabetes and related complications.^9,28 However, cf-mtDNA concentrations are sensitive to pre-analytical handling and assay methodology and may also change with exercise, infection, trauma, and other forms of tissue stress. Consequently, cf-mtDNA remains an investigational marker whose clinical specificity, thresholds, and prognostic utility require prospective validation.

Metabolomic and Proteomic Signatures

Unbiased omics approaches are identifying multi-marker panels that together indicate mitochondrial dysfunction. For instance, a combination of elevated acylcarnitines, certain organic acids (like α-hydroxybutyrate), and inflammatory lipids forms a metabolomic signature that correlates with insulin resistance and incident diabetes. Such signatures aim to capture the systemic ripple effects of mitochondrial inefficiency. On the proteomics side, some groups are looking at circulating levels of mitochondrial proteins — for example, bits of ETC complexes or mitochondrial peptides like humanin and MOTS-c that are released into blood. These small peptides encoded by mtDNA have hormone-like effects and may reflect mitochondrial stress responses; changes in their levels in T2D are under study. Another approach is measuring the oxidative phosphorylation capacity of patient-derived cells (like muscle fibers or blood cells) ex vivo, but this is more of a research tool than a convenient biomarker.

Non-Invasive Imaging

Advanced imaging provides noninvasive physiological readouts but remains primarily investigational. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) can quantify phosphocreatine and ATP-related measures in skeletal muscle; human studies have documented reduced phosphocreatine concentrations and altered bioenergetic profiles in T2D.²⁹ Positron emission tomography (PET) can assess myocardial substrate use and oxidative metabolism, and [11C]acetate studies have reported altered myocardial oxidative metabolism in diabetes.³⁰ Experimental tracers such as [18F]tetraphenylphosphonium can estimate mitochondrial membrane potential,³¹ whereas translocator protein (TSPO) PET primarily reflects inflammatory activation and is not validated as a mitochondrial biomarker for diabetes.³² These methods are valuable for mechanistic phenotyping, but standardization, accessibility, and prospective associations with clinical outcomes remain limited.

No mitochondrial biomarker currently has sufficient disease specificity, standardized thresholds, and prospective validation for routine diagnosis or treatment selection in T2D. Lactate is widely available but nonspecific; acylcarnitine platforms are analytically mature but lack harmonized clinical cutoffs; FGF21 and GDF15 are reproducible stress markers but are influenced by age, renal function, inflammation, and other diseases; cf-mtDNA measurements remain highly sensitive to pre-analytical and assay choices; and platelet or peripheral-blood-cell respirometry is labor-intensive. Accordingly, sensitivity and specificity estimates are not yet stable enough for clinical implementation. The closest candidates to near-term translational use are likely multianalyte panels that combine metabolomic, mitokine, and cellular bioenergetic measures with clinical covariates, but these require external validation, calibration, and demonstration that their use improves decisions or outcomes. Imaging methods such as 31P-MRS provide physiologically meaningful measurements but remain costly and research-oriented.

Taken together, circulating and cellular readouts variably capture mitochondrial stress, content, and function. Table 1 synthesizes emerging biomarkers and their validation maturity to guide selection in future studies.

Table 1.

Emerging Biomarkers of Mitochondrial Dysfunction in Diabetes and Their Evidence Level and Clinical Validation. Validation Classifications Represent the authors’ Synthesis of the Cited Literature Rather Than Formal Consensus Recommendations. No Marker is Currently Validated for Routine Diagnosis or Treatment Selection in T2D

Biomarker	Sample Matrix	What it Reflects	Evidence in T2D Humans	Evidence Level and Clinical Validation
Leukocyte/whole-blood mtDNA copy number (mtDNA-CN)33	Whole blood/leukocytes	Mitochondrial abundance, bioenergetic reserve, and oxidative stress	Associations with insulin resistance and T2D; lower mtDNA-CN has been linked to adverse cardiometabolic outcomes.	Replicated association; assays are available, but pre-analytical variability remains and prognostic utility is under evaluation.
Circulating cell-free mtDNA (ccf-mtDNA)28	Plasma/serum	Cellular/mitochondrial stress, tissue injury, and danger-associated molecular-pattern signaling	Elevated ccf-mtDNA has been reported across diabetes phenotypes, but fractions and assays are heterogeneous.	Exploratory/prognostic evidence; requires harmonized measurement and prospective validation in T2D cohorts.
PBMC/platelet oxygen-consumption rate and OXPHOS complex content34	PBMCs/platelets	Systemic cellular bioenergetic function	Reduced respiration or complex content has been reported in T2D; poorer glycemic control may correlate with worse cellular bioenergetics.	Early human mechanistic evidence; laboratory-intensive and not standardized for routine care. Sensitivity, specificity, and reference ranges are not established.
Mitokines: GDF15 and FGF2135	Plasma	Integrated cellular and mitochondrial stress responses; not specific to mitochondrial dysfunction	GDF15 and FGF21 are often elevated in T2D and may correlate with complication risk.	Well-replicated associations, but neither marker is disease-specific; age-, renal-, and context-dependent thresholds are needed.
Acylcarnitine profiles36	Plasma	Altered fatty-acid handling and substrate oxidation; an indirect and nonspecific indicator of mitochondrial metabolic stress	Distinct profiles are associated with insulin resistance and incident T2D.	Analytical platforms are mature, but clinical cutoffs, specificity, and decision thresholds are not standardized.
Mitochondrial-derived peptides: MOTS-c and humanin35,37	Plasma/serum	Mitochondrial cytoprotective signaling and metabolic resilience	Altered concentrations have been reported in prediabetes and T2D.	Early human associative evidence with substantial preclinical mechanistic support; assay harmonization, independent replication, and prospective longitudinal validation are required before clinical interpretation.
Plasma lipidomic signatures38	Plasma or lipoprotein fraction using advanced lipidomics	Systemic lipid remodeling associated with mitochondrial membrane and substrate-handling abnormalities	Lipidomic signatures have been associated with T2D in people with coronary heart disease, but individual lipid species are not yet clinically interpretable.	Exploratory evidence; requires independent replication, targeted assay validation, and clinically defined thresholds.
Platelet bioenergetic profile panel (respiration and ATP-coupling efficiency)39	Platelets	Circulating-cell mitochondrial performance	Impaired platelet respiration has been reported in metabolic disease.	Early human mechanistic evidence; technically demanding and not standardized for routine care. Clinical reference ranges and incremental value are not established.

Emerging Therapeutics Targeting Mitochondria

The current therapeutic landscape and the translational development pathway for mitochondria-targeted interventions are summarized in Figure 2.

Figure 2.

Evidence-based classification of interventions that influence mitochondrial biology in type 2 diabetes and metabolic syndrome. Panel A presents clinically established interventions—exercise, dietary modification and weight reduction, metformin, GLP-1 receptor agonists, and SGLT2 inhibitors—and proposed effects on mitochondrial biogenesis, redox balance, substrate flexibility, calcium handling, and quality control; these mitochondrial pathways are not proven to mediate all clinical benefits. Panel B presents investigational approaches directed at fusion-fission balance, calcium homeostasis, mitochondrial redox pathways, cardiolipin stabilization, NAD+ metabolism, mitophagy, and autophagy. Elamipretide has early clinical evidence mainly outside T2D; urolithin A has early human evidence, whereas spermidine remains predominantly preclinical; evidence for MitoQ and coenzyme Q10 is limited or mixed. Original figure created by the authors.

Abbreviations: AMPK, AMP-activated protein kinase; DRP1, dynamin-related protein 1; GLP-1, glucagon-like peptide-1; NAD+, nicotinamide adenine dinucleotide; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.

Lifestyle Interventions

Exercise, dietary quality, and sustained weight reduction have the strongest practical evidence among interventions that improve mitochondrial health. Aerobic and resistance exercise increase mitochondrial biogenesis, respiratory capacity, substrate flexibility, and insulin-stimulated glucose disposal.⁵ These effects are clinically established, although mitochondrial adaptation is one component of a broader response involving muscle mass, capillary function, inflammation, and energy balance. Dietary interventions can reduce nutrient overload and ectopic fat; their mitochondrial effects depend on adherence, energy balance, weight change, and baseline metabolic phenotype. Claims that a specific diet directly “repairs” mitochondria should therefore be made cautiously.

The gut microbiome may influence mitochondrial metabolism through short-chain fatty acids, bile acids, and inflammatory mediators, but human causal evidence remains limited. High-quality dietary patterns rich in minimally processed foods, fiber, unsaturated fats, and plant-derived bioactive compounds are clinically reasonable, whereas the incremental mitochondrial benefit of individual supplements or restrictive fasting regimens remains uncertain. Lifestyle interventions should be presented as established components of T2D and metabolic-syndrome management, not as mitochondria-specific therapies.

Pharmacological Interventions

GLP-1 receptor agonists have established glycemic, weight, and cardiovascular benefits in appropriate patients with T2D. Experimental studies suggest mitochondrial effects that include reduced glucolipotoxicity and oxidative stress, improved substrate handling, and activation of AMPK-PGC-1α-related pathways.⁴⁰ However, clinical outcome trials were not designed to establish mitochondrial modulation as the mediator of benefit, and much of the direct organelle-level evidence remains preclinical. GLP-1 receptor agonists should therefore be regarded as clinically established therapies with plausible, but incompletely proven, mitochondria-modulating effects.

SGLT2 inhibitors have established cardiovascular and kidney benefits that extend beyond their glucose-lowering effects. In EMPA-REG OUTCOME, empagliflozin reduced cardiovascular death and hospitalization for heart failure among patients with type 2 diabetes and established cardiovascular disease.⁴¹ In DAPA-HF, dapagliflozin reduced worsening heart failure or cardiovascular death in patients with heart failure and reduced ejection fraction, with similar effects in participants with and without diabetes.⁴² In DAPA-CKD, dapagliflozin reduced sustained kidney-function decline, end-stage kidney disease, or death from renal or cardiovascular causes in patients with chronic kidney disease, regardless of diabetes status.⁴³ Experimental studies additionally suggest that SGLT2 inhibition may reduce renal hypoxia and oxidative stress, alter ketone and fatty-acid utilization, activate AMPK, and improve mitochondrial quality control.⁴⁴ However, these mitochondrial effects coexist with hemodynamic, renal, and systemic metabolic actions, and their relative contribution to the clinical benefits remains uncertain. SGLT2 inhibitors are therefore best regarded as clinically established cardiorenal therapies with possible mitochondria-modulating effects, rather than dedicated mitochondria-targeted drugs.

NAD⁺ precursors reliably increase circulating or tissue NAD-related metabolites in many human studies, demonstrating target engagement.⁴⁵ Metabolic outcomes, however, have been inconsistent: some small trials report improved muscle insulin sensitivity, whereas others show little or no change in glucose regulation, body composition, or physical function. Differences in baseline NAD⁺ status, tissue delivery, dose, duration, and participant phenotype may explain part of this heterogeneity. At present, NAD⁺ boosters remain investigational for T2D and should not be portrayed as established glucose-lowering treatments.

Mitochondria-targeted antioxidants such as MitoQ and elamipretide have strong mechanistic rationale, and experimental studies have demonstrated improvements in oxidative or bioenergetic endpoints in several disease models.^46,47 However, translation to humans has been inconsistent. A systematic review and meta-analysis of randomized human trials evaluating mitochondria-targeted antioxidants, including MitoQ and elamipretide, found limited evidence for glycemic benefit and generally low certainty for most cardiometabolic outcomes.⁴⁸ Evidence for routine use of these agents in T2D therefore remains insufficient.

Mitophagy enhancers such as urolithin A and spermidine are supported mainly by cell and animal studies, with early human studies focused largely on safety, molecular target engagement, or muscle outcomes rather than diabetes control.^49,50 They remain investigational for T2D. Imeglimin has randomized Phase 3 evidence for glucose lowering in Japan and has mitochondrial actions among several proposed mechanisms,^51,52 whereas mitochondrial pyruvate-carrier modulators and other dedicated agents remain in earlier development or have produced mixed results.^53–55

Translational and Clinical Trials

Clinical translation reveals a consistent pattern: biochemical or physiological target engagement is more common than clinically meaningful improvement in glycemia. Established therapies such as exercise, GLP-1 receptor agonists, SGLT2 inhibitors, and imeglimin have clinical efficacy, but their benefits cannot be attributed exclusively to mitochondria. Dedicated mitochondrial agents have generally been tested in small, short-duration, heterogeneous trials and often use surrogate outcomes. Table 2 summarizes the evidence stage and distinguishes randomized human evidence, early human studies, and preclinical candidates.

Table 2.

Clinical-Development Stage and Outcomes of Selected Mitochondria-Modulating Therapies Relevant to T2D. Established Clinical Efficacy Should Not Be Interpreted as Proof That Mitochondrial Effects Mediate Benefit; Investigational Agents are Classified by the Most Mature Human Evidence Identified

Therapy	Primary Mitochondrial Target/Mechanism	Evidence Stage and Population	Design/Duration	Primary Endpoint	Key Outcomes and Interpretation
Imeglimin 1000 mg twice daily51	Modulates mitochondrial bioenergetics, glucose-stimulated insulin secretion, insulin sensitivity, and oxidative stress	Randomized Phase 3 evidence; Japanese adults with T2D	Double-blind, placebo-controlled; 24 weeks	Change in HbA1c	Reduced HbA1c vs placebo and was generally well tolerated. Clinical efficacy is established in the studied setting, but mitochondrial mediation is not proven.
Imeglimin plus insulin56	Same proposed mechanisms	Randomized Phase 3 evidence; Japanese adults with T2D receiving insulin	Double-blind, placebo-controlled; 16 weeks plus 36-week extension	Change in HbA1c	Improved HbA1c when added to insulin, with sustained effect in the extension.
Imeglimin monotherapy or combinations52	Same proposed mechanisms	Phase 3 long-term open-label evidence; Japanese adults with T2D	Open-label; 52 weeks	Safety and efficacy	Sustained HbA1c improvement and acceptable safety over 52 weeks; the open-label design limits comparative inference.
MSDC-0160 (mitoglitazone)54	Mitochondrial pyruvate-carrier/mTOT modulation with insulin-sensitizing effects	Randomized Phase 2 proof-of-concept; adults with T2D	Active- and placebo-controlled; 12 weeks	Change in HbA1c	Lowered HbA1c vs placebo; broader confirmation and clinical-development evidence remain limited.
MSDC-0602K55	Mitochondrial pyruvate-carrier modulation	Randomized phase 2b evidence in steatohepatitis; many participants had T2D	Double-blind; 52 weeks	Histologic NASH endpoint	The primary composite histologic endpoint was not met; higher doses reduced glucose, HbA1c, and insulin. This is mixed rather than definitive T2D evidence.
BGP-1553	Heat-shock-protein co-induction and mitochondrial stress protection	Early randomized proof-of-concept; insulin-resistant participants; limited public T2D results	Short-duration randomized studies	Insulin sensitivity and glycemic measures	Improved insulin sensitivity in an early proof-of-concept study; evidence is insufficient for routine T2D use.
Coenzyme Q10 adjunct57	Electron-transport-chain cofactor and antioxidant	Meta-analysis of small randomized trials in T2D	Generally 8–24 weeks	Glycemic and lipid markers	Pooled analyses suggest modest glycemic effects, but heterogeneity and mixed individual-trial results limit certainty.
MitoQ48	Mitochondria-targeted ubiquinone antioxidant	Early human cardiometabolic evidence; insufficient T2D-specific randomized evidence	Small, short-term studies	Vascular or bioenergetic outcomes	Human randomized evidence does not demonstrate a consistent glycemic benefit. Available studies are small and heterogeneous; evidence for routine T2D use is insufficient.

Several factors may explain why animal results underperform in humans. Experimental models often use young, genetically homogeneous animals, high compound exposures, and interventions initiated before advanced disease. Human T2D is chronic, heterogeneous, and shaped by age, adiposity, comorbidities, polypharmacy, and variable mitochondrial phenotypes. Tissue delivery may be inadequate, mitochondrial dysfunction may be secondary rather than causal, and broad suppression of ROS may interfere with physiological redox signaling. Trials may also be underpowered, too short, or focused on HbA1c despite an intervention primarily affecting muscle function, vascular physiology, or organ protection. Negative and neutral findings are therefore informative and argue for phenotype-enriched trial designs rather than indiscriminate use.

The therapeutic evidence base is limited by small samples, short follow-up, inconsistent mitochondrial endpoints, and scarce replication by independent groups. Many interventions are pleiotropic, making mediation difficult to establish. The targeted search strategy used in this narrative review may also preferentially identify prominent compounds and positive reports. These limitations reduce confidence in claims of class-wide efficacy and reinforce the need to distinguish hypothesis-generating evidence from practice-changing evidence.

Future trials should prespecify mitochondrial target engagement, clinically relevant outcomes, and the hypothesized causal pathway; use validated and reproducible biomarker panels; include adequate duration and sample size; and stratify or enrich enrollment by baseline mitochondrial phenotype. Adaptive or biomarker-guided designs may help determine whether a treatment benefits a definable subgroup rather than the broad T2D population.

Integrating Mitochondrial Dysfunction into the “Multiple-Hit” Model of T2D

A bidirectional multiple-hit model best reconciles the available evidence. Genetic susceptibility, aging, physical inactivity, visceral adiposity, nutrient excess, dysbiosis, inflammation, hyperglycemia, and lipotoxicity can each impair mitochondrial respiration, quality control, calcium handling, or redox balance. Mitochondrial stress then amplifies these initiating factors through incomplete substrate oxidation, ROS generation, release of mitochondrial danger signals, altered organelle communication, and reduced metabolic flexibility. This model avoids treating mitochondrial dysfunction as either universally primary or merely epiphenomenal.

The same network recurs across tissues. In adipose tissue, mitochondrial stress and cell expansion promote inflammatory signaling and excess fatty-acid release. In liver and muscle, fatty-acid oversupply, diacylglycerol, ceramides, and altered calcium handling disrupt insulin signaling. In β-cells, glucolipotoxicity, endoplasmic-reticulum stress, calcium imbalance, and defective mitophagy impair stimulus-secretion coupling and survival. Mitochondrial ROS and mtDNA can activate the NLRP3 inflammasome, while inflammatory cytokines further impair electron transport and dynamics. Aging lowers bioenergetic reserve and quality-control capacity, increasing vulnerability to each additional hit.

The multiple-hit model links the mechanistic, biomarker, and therapeutic evidence and explains why a single mitochondrial biomarker or drug is unlikely to apply uniformly. Different patients may reach a similar glycemic phenotype through different combinations of mitochondrial and nonmitochondrial abnormalities.

Critical Synthesis, Limitations, and Future Directions

The strongest conclusion supported by current evidence is not that mitochondrial dysfunction is the sole root cause of T2D, but that it is a variable and potentially modifiable component of a broader pathophysiological network. Human studies demonstrate mitochondrial abnormalities in relevant tissues, yet temporal direction and independence from age, adiposity, fitness, and glycemic exposure remain difficult to establish. Some studies identify reduced mitochondrial content or respiration before overt diabetes, whereas others show preserved or compensatory oxidative activity. These findings are compatible with biologically distinct T2D subtypes and disease stages.

The evidence base has important limitations. Mitochondrial measurements differ across tissues and laboratories; muscle-biopsy results may not represent liver, adipose tissue, myocardium, or β-cells. Many biomarkers are nonspecific and influenced by exercise, renal function, inflammation, medication, and sample processing. Clinical trials are frequently small and short, and few require baseline evidence of mitochondrial dysfunction. The present review is also limited by its narrative design, targeted search terms, absence of a PRISMA flow diagram, formal risk-of-bias assessment, and standardized evidence grading. Because complete historical database-specific search strings, record-level search logs, search yields, duplicate counts, and reasons for exclusion were not prospectively retained, the review cannot provide systematic-review-level reproducibility or a quantitative study-selection flow. In addition, deliberate inclusion of named therapeutic compounds may have preferentially retrieved prominent agents and underrepresented competing interventions or neutral and negative studies indexed under other terminology. The review may therefore be affected by selection and publication bias and cannot claim systematic completeness.

Priority research needs include prospective validation of multianalyte mitochondrial biomarker panels; standardized pre-analytical and analytical procedures; comparison against tissue-level or functional reference measures; and evaluation of incremental value beyond routine clinical variables. Trials of mitochondria-directed therapies should be adequately powered, include longer follow-up, report negative and neutral outcomes, and distinguish target engagement from glycemic, cardiovascular, renal, functional, and patient-reported benefits.

Mitochondrial phenotyping may ultimately support precision medicine, but clinical utility must be demonstrated rather than assumed. A useful test must classify a reproducible biological phenotype, predict prognosis or treatment response, and improve outcomes when used to guide care. Until those conditions are met, mitochondrial biomarkers and advanced imaging should remain research tools.

The most actionable near-term strategy is to integrate mitochondrial endpoints into trials of established lifestyle and pharmacological interventions while developing phenotype-enriched studies of dedicated mitochondrial agents. This approach can clarify mediation, identify responders, and prevent premature clinical adoption based solely on preclinical promise.

Conclusion

Mitochondrial dysfunction contributes to insulin resistance, β-cell failure, and cardiometabolic injury through interacting defects in oxidative phosphorylation, redox balance, organelle quality control, calcium signaling, and substrate flexibility. The evidence supports a bidirectional role: mitochondrial abnormalities can increase vulnerability to metabolic disease, while hyperglycemia, visceral adiposity, lipotoxicity, inflammation, aging, and inactivity can cause or deepen mitochondrial impairment.

Clinically established interventions—including exercise, sustained weight reduction, GLP-1 receptor agonists, and SGLT2 inhibitors—may improve mitochondrial biology as part of their broader benefits. Dedicated mitochondrial antioxidants, NAD⁺ boosters, mitophagy enhancers, and related agents remain preclinical or investigational for routine T2D care, with inconsistent glycemic effects despite frequent evidence of target engagement. The next steps are concrete: validate reproducible biomarker panels against functional reference measures, conduct larger and longer randomized trials with prespecified mitochondrial and clinical outcomes, and prospectively identify patients most likely to respond. Mitochondrial phenotyping could advance precision care only after it demonstrates added predictive and treatment-guiding value beyond established clinical measures.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Generative AI and AI-Assisted Technologies

ChatGPT (OpenAI; GPT-5.5 and GPT-5.6 SoL; accessed in 2026) was used after preparation of the authors’ initial draft to assist with language refinement, grammar, sentence clarity, organization, and formatting. It was not listed as an author and was not used to make autonomous scientific decisions. All substantive content, interpretations, citations, and revisions were critically reviewed, verified, and approved by the authors, who accept full responsibility for the originality, accuracy, integrity, and final content of the manuscript.

Abbreviations

AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; Ca²⁺, calcium ion; cf-mtDNA/ccf-mtDNA, circulating cell-free mitochondrial DNA; CoQ/CoQ10, coenzyme Q/coenzyme Q10; DAG, diacylglycerol; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; ETC, electron transport chain; FAO, fatty acid oxidation; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; GLP-1 RA, glucagon-like peptide-1 receptor agonist; GSIS, glucose-stimulated insulin secretion; HbA1c, glycated hemoglobin; IMM, inner mitochondrial membrane; MAMs, mitochondria-associated membranes; MCU, mitochondrial calcium uniporter; MFN1/2, mitofusin 1 and 2; MitoQ, mitochondria-targeted ubiquinone; MOTS-c, mitochondrial open reading frame of the 12S rRNA-c; MRI, magnetic resonance imaging; mtDNA, mitochondrial DNA; NAD⁺, nicotinamide adenine dinucleotide; NAFLD, nonalcoholic fatty liver disease; NRF-1/2, nuclear respiratory factor 1 and 2; OXPHOS, oxidative phosphorylation; PBMCs, peripheral blood mononuclear cells; PCr, phosphocreatine; PET, positron emission tomography; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PKC, protein kinase C; ROS, reactive oxygen species; SGLT2i, sodium-glucose cotransporter 2 inhibitor; SIRT1/3, sirtuin 1 and 3; T2D, type 2 diabetes; TCA, tricarboxylic acid; TSPO, translocator protein.

Data Sharing Statement

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current narrative review.

Author Contributions

Hamzah M. Alghzawi: Conceptualization, Methodology, Investigation, Writing — original draft, Writing — review & editing, Supervision, Project administration.

Salma Younas: Investigation, Writing — original draft, Writing — review & editing.

Sweta Sahu: Investigation, Writing — original draft, Writing — review & editing.

Soha Farooq: Investigation, Writing — original draft, Writing — review & editing.

Muhammad Nafees: Investigation, Writing — original draft, Writing — review & editing.

Saleh Mohammed: Investigation, Writing — original draft, Writing — review & editing.

All authors took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.