From the energy factory to the intercellular communication medium: the emerging role of intercellular mitochondrial transfer and mitochondrial transplantation therapy in diabetes and diabetic complications

Abstract

Background

Diabetes is a global chronic metabolic disorder that frequently results in multiple chronic complications. However, current therapeutic agents for diabetes and its complications fail to alleviate the core pathological process of mitochondrial dysfunction in affected target organs, rendering them incapable of fundamentally retarding the progression of these complications.

Mainbody

Mitochondrial transfer is a novel type of intercellular communication. Mitochondria can be transferred between cells and improve mitochondrial dysfunction in either the donor cell or the recipient cell. Accumulating evidence indicates that mitochondrial transfer exerts multiple regulatory effects to delay the progression of diabetes and its complications, including promoting insulin secretion, improving insulin resistance, facilitating the migration of vascular endothelial cells, and enhancing mitochondrial function in renal parenchymal cells. This review systematically summarizes the characteristics and molecular mechanisms of mitochondrial transfer, explores its pathophysiological implications in diabetes and related complications, and briefly discusses the application prospects of mitochondrial transplantation therapy in the management of diabetes and its complications based on the mitochondrial transfer theory.

Conclusions

This review offers valuable insights and novel research directions for the design of innovative therapeutic strategies targeting diabetes and its complications.

Introduction

Diabetes mellitus (DM) is one of the most prevalent chronic diseases worldwide, and is characterized by insufficient insulin secretion and/or insulin resistance [1]. According to the 2025 report from the International Diabetes Federation (IDF), the global adult population with diabetes has reached approximately 589 million, and this number continues to rise [2, 3]. Patients with diabetes often develop a spectrum of chronic complications including diabetic kidney disease (DKD), diabetic cardiomyopathy (DCM), diabetic neuropathy, and diabetic foot [4–6]. These complications substantially impair the prognosis and quality of life of DM patients. Current research suggests that the pathogenesis of diabetes and its associated complications is associated with glycolipid toxicity, oxidative stress, neutrophil extracellular traps (NETs), ferroptosis, and endoplasmic reticulum (ER) stress [7–10]. Furthermore, the integrity of mitochondrial function and the mitochondrial quality control (MQC) system are also crucial factors influencing the pathological process of diabetes and its complications [11–13].

Mitochondria, double membrane-bound organelles present in eukaryotic cells, are indispensable for a variety of essential physiological processes. Although their primary and most well-recognized function is the generation of adenosine triphosphate (ATP) via metabolic pathways, they also participate in numerous physiological mechanisms, including the regulation of Ca²⁺ homeostasis, copper metabolism, cellular signal transduction, modulation of programmed cell death, facilitation of antiviral immune responses, promotion of cell proliferation, and maintenance of redox balance [14–19]. Traditionally, mitochondria are believed to localize exclusively in the cytoplasm and are inherited solely from parental cells through a process termed vertical mitochondrial inheritance [20]. However, surprisingly, cells not only can replicate their own mitochondria but also can transfer them to other cell types through various pathways. This phenomenon is called horizontal or intercellular mitochondrial transfer [21–23]. Researchers have begun to pay increasing attention to this novel type of intercellular signal communication. Studies have shown that mitochondrial transfer is actually a form of MQC, widely present in inflammation, cell aging and death, oxidative stress, calcium signal transduction and other physiological processes (Fig. 1), and is closely related to the progression of various diseases, such as cerebral ischemia-reperfusion (I/R) injury, cranial neuritis, osteoporosis and rotator cuff injury [24–29]. Not only that, recent studies over the past five years have shown that mitochondrial transfer also plays a crucial role in the physiological regulation and pathological development of DM and its complications through multiple mechanisms (Fig. 2).

Fig. 1.

The main research directions of mitochondrial transfer. Over the past 15 years, the keywords reported in the field of mitochondrial transfer have been displayed in different font sizes. The larger the font size, the more times the keyword has been reported

Fig. 2.

Research progress on mitochondrial transfer in diabetes and its complications. Since 2019, an increasing number of related studies have reported the role of mitochondrial donor cells such as MSCs in mediating mitochondrial transfer in diabetes and its complications

The traditional treatment methods for DM and its complications (such as oral hypoglycemic drugs and insulin injections), which can only control blood glucose levels but cannot rapidly reverse the core pathological changes, such as the failure of pancreatic β-cell function and mitochondrial dysfunction in target organs [30–31]. Therefore, systematically elucidating the regulatory mechanism of intercellular mitochondrial transfer in the pathogenesis and progression of diabetes is expected to provide a new perspective for the development of targeted therapeutic strategies for diabetes and its complications.

Previous published reviews have comprehensively explored the relationship between mitochondrial transfer and the mitochondrial quality control system [32], the characteristics and mechanisms of mitochondrial transfer [22], and how mitochondrial dysfunction that occurs in DM triggers mitochondrial transfer [33]. In this review, we will not elaborate on the above points in detail. Our study aims to conduct a detailed analysis of the critical roles, regulatory mechanisms, and research limitations of mitochondrial transfer in the pathological microenvironment of diabetes. We also provide a supplementary discussion on the application value of mitochondrial transplantation therapy in diabetes and its complications. Collectively, this review not only reveals the broad prospects of innovative diabetes therapies targeting mitochondrial transfer but also lays a solid theoretical foundation for the exploration and clinical application of mitochondrial transfer-related biomarkers in the early diagnosis of chronic diabetic complications.

The characteristics of mitochondrial transfer

Mitochondrial transfer is an evolutionarily conserved process that occurs not only in animal cells, but also in yeast and plant cells [34]. Notably, this phenomenon occurs under both pathological conditions (e.g., diabetes, leukemia, acute lung injury, asthma, and cancer) and normal physiological processes [35–39]. Mitochondrial transfer can occur between cells of the same or different types within a single organ or between heterotypic cells across distant tissues, with the blood, cerebrospinal fluid, and lymph serving as potential transfer conduits [40–42]. Intercellular mitochondrial transfer networks exist in which cells of the same type can act as both mitochondrial donors and recipients. Furthermore, a single cell may engage in multiple mitochondrial transfer pathways, which can proceed either sequentially or concurrently [43]. Although mitochondrial transfer can be triggered by various intracellular and extracellular stimuli, including high-glucose environments, hypoxia, oxidative stress, and cellular inflammation [44–46], the specific intracellular signaling pathways, biological mechanisms involved, and effects of donor cell mitochondria on recipient cells remain poorly understood.

There are two primary types of mitochondrial transfer. The first involves the transfer of healthy mitochondria from donor cells to recipient cells to enhance the latter's mitochondrial function. The second involves the transfer of damaged mitochondria from donor cells to recipient cells (such as macrophages, astrocytes, cardiomyocytes, fibroblasts, and T cells), clearing the damaged mitochondria through transmitophagy, or directly integrating them into the mitochondrial network of the recipient cell, thereby alleviating the mitochondrial dysfunction of the donor cell [47]. The release of damaged mitochondria may be a compensatory mechanism that occurs when the cell is under stress, and their endogenous mitophagic capacity is insufficient to cope with the damaged mitochondria.

The mechanism of mitochondrial transfer

Recent studies have classified the mechanisms or pathways underlying intercellular mitochondrial transfer into two primary categories: contact-dependent mechanisms, which include tunneling nanotubes (TNTs) and cell adhesion, and noncontact-dependent mechanisms, which involve the transfer of extracellular vesicles (EVs) and free mitochondria [Figure 3]. It is critical to recognize that the identification of a specific transfer mechanism does not rule out the potential involvement of other mechanisms, as intercellular mitochondrial transfer may utilize multiple mechanisms concurrently [48]. Unfortunately, so far only EVs and TNTs have been identified in association with DM and its complications. The hierarchical dominance and reciprocal interplay of these two mechanisms across distinct tissue types in DM and its associated complications remain largely undefined. At present, further research is needed to determine whether there are other unidentified mechanisms of mitochondrial transfer in the diabetic microenvironment.

Fig. 3.

The mechanisms of mitochondrial transfer. There are various pathways through which donor cells transfer mitochondria to recipient cells. The donor cells can participate in the formation of multivesicular bodies (MVBs) through the Golgi apparatus and release extracellular vesicles (EVs) encapsulating the mitochondria, directly transport via TNTs, or transfer the mitochondria through cell gap junctions and the release of free mitochondria. After receiving the mitochondria, some undergo mitochondrial fusion to integrate into their own mitochondrial network, while others are encapsulated by autophagosomes and combined with lysosomes for degradation through mitophagy, resulting in fragmentation. Meanwhile, whether the free mitochondria “escape” from degradation after entering the recipient cells remains to be further investigated

Tunneling nanotubes

TNTs are membranous tubular structures composed of F-actin that connect two cells and represent the most frequently reported contact-dependent mechanism of mitochondrial transfer [49]. The diameters of the TNTs range approximately from 0.5 to 1.5 μm. By maintaining open ends in both connected cell types, TNTs can mediate the transfer of intracellular components (such as α-synuclein, Ca²⁺, viral and bacterial pathogens) and cellular organelles between cells [50–53]. Additionally, TNT-mediated mitochondrial transfer can occur in a unidirectional or bidirectional manner. Although recent studies have indicated that inflammation, reactive oxygen species (ROS) accumulation, and metabolic demands are key triggers for TNTs initiation [54–56], the specific mechanisms that regulate TNTs formation remain elusive. Furthermore, the co-culture method between mitochondrial donor cells and recipient cells significantly affects the efficiency of TNTs formation. For instance, studies have demonstrated that co-culturing MSCs with endothelial cells in a dynamic 3D co-culture system using gelatin microcryogel microcarriers enhances TNTs-mediated mitochondrial delivery efficiency between MSCs and endothelial cells [57].

Gap junctions

Another contact-dependent mechanism of mitochondrial transfer involves the gap junction protein connexin 43 (CX43), which is referred to as the cell gap junctional channel-mediated mitochondrial transfer. CX43 facilitates adhesion between two cells; however, its pores are extremely small, precluding the transfer of large cargo such as mitochondria between cells directly through this protein. Instead, CX43 enables recipient cells to acquire mitochondria from donor cells via the formation of gap junction vesicles and subsequent endocytosis [58–59]. Notably, TNTs can also be formed at CX43-containing contact sites [60]. Therefore, when observing mitochondrial transfer mediated by cell adhesion, it is essential to determine whether TNTs coexist with and contribute to this process. Cellular oxidative stress and other related states may be triggering factors that regulate the opening of gap junction protein channels and enable the mitochondria transfer between cells [61].

Extracellular vesicles

EVs are phospholipid bilayer membranous structures that are actively released by cells, and they can be secreted by almost all cell types [62]. Their diameters range from 30 nm to 5 μm, and they can carry intercellular transport lipids, functional proteins, microRNAs, and organelles (such as mitochondria) to mediate long-distance intercellular signal communication [63]. At present, the methods for identifying and characterizing EVs mainly rely on detection by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and detection of characteristic marker proteins of EVs, such as membrane proteins CD9, CD63, and CD81 and their matrix protein TSG101 through Western blotting [64]. Mitochondria-associated extracellular vesicles (Mito-EVs) represent a distinct subtype of EVs, exhibiting pronounced heterogeneity in both size and cargo composition. Their diameters range from approximately 50 nm to 8 μm, the core hallmark of Mito-EVs lies in their enrichment with mitochondria-derived components, including mitochondrial DNA (mtDNA), mitochondrial proteins, and even intact mitochondria. By shuttling these mitochondrial cargos between cells, Mito-EVs modulate the metabolic status, immune responses, and other biological functions of recipient cells [65]. Regrettably, at present, there is still a lack of universal and specific surface markers applicable for the identification of Mito-EVs, so this has become a pressing challengein this field. In addition, the currently recognized Mito-EVs isolation methods have several drawbacks, such as susceptibility to impurity contamination and excessive experimental costs, highlighting the imperative need to develop more efficient approaches for extracting high-purity Mito-EVs. Furthermore, the precise classification and more standardized definition of Mito-EVs based on their size and cargo composition should also be prioritized as key focal points of future research.

Free mitochondria transfer

The fourth principal mechanism of intercellular mitochondrial transfer involves the release of free mitochondria by donor cells, which are subsequently internalized by the recipient cells. The origins of free mitochondria in the bloodstream vary, encompassing sources such as platelets and adipocytes [66]. The intracellular mechanisms that regulate the release of free mitochondria remain unclear at present, free mitochondria may partially originating from the mitochondria in donor cells that cannot be cleared by autophagy. Since free mitochondria do not have protein markers related to EVs, only mitochondrial proteins such as TOM20 can be detected. Thus, free mitochondria and Mito-EVs in body fluids can be distinguished through western blotting. The capture of free mitochondria by recipient cells is achieved through processes such as endocytosis or microphagy; for example, macrophage subtypes with high expression of TREM2 can phagocytose free damaged mitochondria released by myocardial cells of septic mice, improving excessive inflammation in the myocardium [67]. However, the destination of the free mitochondria after capture by the recipient cells requires further study.

Notably, the fate of donor-derived mitochondria following their entry into recipient cells via the aforementioned four transfer mechanisms is predominantly governed by the recipient’s cellular functional status, microenvironmental factors, and the intrinsic quality of the transferred mitochondria themselves [22]. At present, there are no relevant studies that have investigated whether the fate of donor cell mitochondria within the recipient cells is affected by these transfer mechanisms. Upon entering recipient cells, functionally intact donor mitochondria integrate into the host mitochondrial network via membrane fusion, thereby contributing to ATP biosynthesis and mediating energy metabolic cascades. In contrast, mitochondria with compromised integrity or severe structural damage are prone to being cleared by the recipient’s mitophagic machinery [39]. However, it is not clear whether the damaged mitochondria entering the recipient cells can be re-excreted from the recipient cells or partially escape the fate of lysosomal degradation by the recipient cells.

Mitochondrial transplantation therapy

Mitochondrial transplantation is an artificial therapeutic technology based on the natural phenomenon of intercellular mitochondria transfer. It refers to a targeted intervention strategy that delivers isolated and purified healthy mitochondria (derived from autologous, allogeneic, or stem cell sources) into diseased cells or tissues through artificial intervention methods [Fig. 4]. The primary goal is to repair mitochondrial functional defects and treat related disorders, including mtDNA mutation-related diseases and I/R injury [68–69]. The fundamental distinction between mitochondrial transplantation and mitochondria transfer lies in that the former is a human-led, therapeutically oriented active intervention technology, whereas the latter is a naturally occurring biological process autonomously regulated by cells to serve the body’s intrinsic homeostatic regulation [70]. Mesenchymal stem cells (MSCs) have emerged as the most widely used donor cells for mitochondrial transplantation owing to their broad distribution across various tissues, ease of acquisition, low immunogenicity, minimal energy requirements, and robust disease-targeting abilities [71]. The beneficial effects of mitochondria derived from MSCs on recipient cells have been fully verified in various organ systems, including the skeletal muscle, nervous system, immune system, cardiovascular system, and respiratory system [72–76].

Fig. 4.

The process of mitochondrial transplantation. Extract tissue homogenates or cell supernatants from skeletal muscle tissues or various stem cells, including bone marrow mesenchymal stem cells (BMSCs), umbilical cord mesenchymal stem cells (UC-MSCs), induced pluripotent stem cells (iPSCs), etc. Through differential centrifugation technology, separate free mitochondria and mitochondrial vesicles from the tissue homogenates or cell supernatants. Apply the isolated mitochondria to cell experiments and animal model experiments to complete the mitochondrial transplantation process

Although mitochondrial transplantation represents a promising therapeutic strategy for mitochondrial diseases, it still faces multiple non-negligible challenges in terms of safety, technical implementation, and clinical translation. For instance, allogeneic mitochondrial components (e.g., mtDNA) can trigger the innate immune pathways of recipient tissue cells, leading to immune cell activation and pro-inflammatory cytokine release. At present, there is a lack of standardized manufacturing protocols for mitochondrial transplantation, and the quality control criteria (e.g., viability, purity, sterility) for mitochondria have not yet been unified. Should suboptimal or damaged mitochondria be introduced due to flawed isolation processes, this may conversely exacerbate mitochondrial metabolic disorders in recipient cells. Furthermore, the viability of isolated mitochondria declines rapidly, and the freeze-thaw cycle often induce mitochondrial swelling and cristae structural damage, thereby impairing respiratory chain function and ATP synthesis capacity. Current mitochondrial delivery approaches (e.g., intravenous injection) fail to achieve precise targeting of pathological tissues, which often results in mitochondrial accumulation at non-target sites. Most importantly, the sourcing of allogeneic mitochondria raises ethical concerns regarding donor selection, while the ethical review framework for mitochondrial transplantation remains inadequately established.

The role of mitochondrial transfer in diabetes

Type 1 diabetes mellitus

The essence of type 1 diabetes mellitus (T1DM) is the progressive destruction and complete failure of pancreatic β cells, resulting in absolute insulin deficiency in the body. Recent work by the Rackham group has demonstrated that in vitro co-culture of adipose-derived mesenchymal stem cells (AD-MSCs) with isolated human or mouse pancreatic islet cells significantly enhanced mitochondrial aerobic respiration in β-cells and promoted insulin secretion. The study further revealed that the majority of MSC-derived mitochondria were localized in β-cells, with a small fraction detected in pancreatic α-cells, δ-cells, and endothelial cells. Collectively, these findings indicate that mitochondrial transfer from AD-MSCs to islet cells exerts a multitarget effect and positively modulates β-cell function [77]. As pancreatic islet endothelial cells are a critical component of the islet microenvironment, their functional integrity—encompassing vascular permeability, nutrient transport, and inflammatory regulation—directly influences the metabolic state and secretory function of β-cells. Therefore, whether mitochondria transfer from MSCs to endothelial cells can repair endothelial cell dysfunction, thereby creating a favorable microenvironment for β-cell insulin secretion and ensuring β-cells’ rapid sensing of blood glucose fluctuations, remains to be further verified. The researchers also discovered that both EVs and TNTs are involved in the mitochondrial transfer between AD-MSCs and β cells by using Mito-GFP labeling and phalloidin staining. Notably, the in vitro co-culture approach adopted in this study entailed direct contact and monolayer culture of AD-MSCs and islet cells. However, under physiological conditions, these two cell types are spatially distant from each other, which precludes the formation of TNTs structures between them. Therefore, the observed intercellular mitochondrial transfer events derived from this direct-contact co-culture system warrant further validation via Transwell-based indirect co-culture assays and in vivo experiments. Future studies can explore more efficient strategies for delivering the mitochondria of MSCs to β cells, with the aim of improving the clinical outcomes in patients with T1DM. Additionally, investigating how high-glucose/high-fat cellular microenvironments regulate mitochondrial transfer between MSCs and β cells is of critical importance. Moreover, investigating whether mitochondrial transfer between MSCs and α-cells contributes to the regulation of glucagon secretion could provide valuable insights for the prevention and treatment of diabetes.

Type 2 diabetes mellitus

One notable study has uncovered potential links between mitochondrial transfer and the development of insulin resistance, a key feature of type 2 diabetes mellitus (T2DM). Hypothalamic neurons expressing proopiomelanocortin (POMC) play a pivotal role in regulating systemic glucose homeostasis [78–79]. Yin et al. demonstrated that short-term high-fat diet (HFD) feeding in mice, combined with overexpression of the serine/threonine protein kinase Tak1 in astrocytes of the mediobasal hypothalamus (MBH), promotes mitochondrial transfer from astrocytes to POMC neurons within the hypothalamus. This transfer process enhanced the glucose-sensing capacity of POMC neurons and improved HFD-induced insulin resistance and abnormal glucose tolerance [80]. Although this study is the first to establish a link between mitochondrial transfer and central nervous system (CNS)-mediated regulation of glucose metabolic homeostasis, it has several limitations. In this study, a mouse model of insulin resistance was established via 4-week consecutive HFD feeding, which only recapitulates the early-stage insulin resistance state characterized by the absence of significant elevation in fasting blood glucose levels. Therefore, further investigations are required to clarify how the ability of astrocytes to transfer mitochondria to hypothalamic neurons changes as HFD feeding is prolonged and streptozotocin (STZ) is administered—conditions that progressively lead to T2DM. Furthermore, the mechanism by which mitochondria derived from astrocytes affect the function of POMC neurons also needs to be further clarified.

In addition to the discovery that insulin resistance may be related to the phenomenon of mitochondrial transfer, a recent study also explored the application value of mitochondrial transplantation therapy in improving insulin resistance. Kim et al. isolated functional mitochondria from C2C12 skeletal muscle cells via centrifugation and subsequently transplanted these mitochondria into palmitic acid (PA)-treated C2C12 cells. This intervention effectively ameliorated insulin resistance, enhanced glucose uptake capacity, and restored mitochondrial ATP synthesis in the recipient cells [81]. Given that this mitochondrial transplantation method seems to have significant therapeutic effects, future research should further explore whether it is possible to artificially introduce mitochondria from other more accessible donor cell sources (such as MSCs) into liver tissue and skeletal muscle tissue through mitochondrial transplantation in order tonull improve insulin resistance.

The role of mitochondrial transfer in diabetic complications

Chronic diabetic wounds

Chronic diabetic wounds are non-healing injuries resulting from diabetes-related complications including neuropathy, vascular impairment, infection, and skin ulcers. Diabetic foot ulcers are the most prevalent [82–83]. Angiogenesis and blood supply reconstruction play pivotal roles in the complex wound-healing process. As essential components of the blood vessel walls, the structural integrity and functional competence of vascular endothelial cells directly determine the efficiency of neovascularization.

Hao et al. developed a novel biohydrogel “SG/M” by incorporating Mdivi-1—a mitochondrial fission and autophagy inhibitor—into silk fibroin/gelatin (SG). In STZ-induced hyperlipidemic diabetic rats, SG/M hydrogel significantly accelerated wound repair. When THP-1 cells treated with Mdivi-1 were co-cultured with human umbilical vein endothelial cells (HUVECs) in a high glucose medium, the mitochondria of THP-1 cells would transfer to the HUVECs. This transfer improved HUVEC migration capacity and mitochondrial membrane potential while reducing ROS production [84]. Similarly, another study on novel materials has also identified the transfer of mitochondria between M2 macrophages and endothelial cells as a key pharmacological mechanism. The researchers developed a WOC nanomedicine via the coordination-driven assembly of tungstate anions (WO₄²⁻) and chitosan oligosaccharide (COS). When applied to dorsal skin wounds of STZ-induced diabetic rats, WOC significantly promoted epidermal regeneration, granulation tissue proliferation, and neovascularization. When WOC-treated RAW264.7 cells were co-cultured with H₂O₂-injured HUVECs, the survival rate of HUVECs and their capacity to form tubular structures were significantly improved. Furthermore, they discovered through TEM that WOC may stimulate macrophages to release microvesicles (a subtype of EVs) containing mitochondria [85]. Although both of these two studies have established a complete evidence chain ranging from therapeutic efficacy in animal models to the underlying mechanisms at the cellular level, their in vitro cellular assays merely recapitulated the characteristic features of hyperglycemia and oxidative stress-induced damage seen in diabetes, while failing to take into account other critical pathophysiological perturbations present in diabetic patients, such as the chronic inflammatory microenvironment and lipid metabolic disorders. This limitation may lead to discrepancies between the observed mitochondrial transfer phenomena in cellular experiments and the actual conditions in vivo.

Excessive production of NETs in diabetic wounds can induce ferroptosis in vascular endothelial cells and inhibit angiogenesis at diabetic lesion sites [86–88]. Lu et al. discovered that EVs derived from mesenchymal stem cells (MSC-EVs) could restore mitochondrial function in neutrophils by transferring functional mitochondria, thereby accelerating wound healing and suppressing NETs formation. Notably, by completely impairing the function of mitochondria within MSC-EVs, the therapeutic effect of MSC-EVs was completely eliminated [89]. Although this finding provides a novel therapeutic strategy for diabetic wound management, the study has limitations: its short experimental duration and use of STZ-induced T1DM mice, whereas chronic diabetic wounds predominantly occur in T2DM patients. Additionally, studies have shown that plasma concentrates contain platelet-released free mitochondria and mitochondrial components that are encapsulated in EVs. These platelet-derived mitochondria can be phagocytosed by HUVECs, thereby reducing oxidative stress-induced apoptosis and mitochondrial dysfunction [90]. However, it remains to be clarified whether the mitochondrial transfer phenomenon between platelets and HUVECs is related to the repair of vascular endothelial cell damage in diabetic wounds. Furthermore, the potential regulatory role of mitochondrial transfer in local nerve cell function repair, fibroblast proliferation and activation in chronic diabetic wounds should deserves attention.

Diabetic kidney disease

Proximal tubule epithelial cells (PTECs) are responsible for reabsorption of glucose, amino acids, proteins, and other substances from the glomerular filtrate. Under diabetic conditions, PTECs exhibit impaired reabsorptive function, cellular hypertrophy, apoptosis, and the initiation of renal interstitial fibrosis [91–92]. Research by Naoto Kobayashi et al. demonstrated that bone marrow mesenchymal stem cells (BMSCs) can effectively mitigate diabetes-induced oxidative stress damage and apoptosis of PTECs via mitochondrial transfer mechanisms. In this research, BMSCs were transfected with a lentiviral vector encoding the mitochondrial fluorescent protein DSRed2 and then administered to STZ-induced diabetic mice via tail vein injection or renal capsule implantation. Subsequent findings revealed the presence of DSRed2-positive mitochondrial signals in PTECs. Additionally, in vitro studies have shown that mitochondrial transfer from BMSCs to PTECs significantly improves cellular morphology and oxygen consumption rates, while downregulating the expression of SOD2 and Bcl-2 [93]. Notably, this study failed to explicitly detect the distribution efficiency of mitochondria in the circulation during the BMSCs tail vein injection experiments. In in vitro experiments, NRK-52E cells were only exposed to a 55 mM high concentration of glucose, which was much higher than the glucose concentration that the cells were exposed to in their in vivo microenvironment and no concentration gradient was set. This resulted in the inability to establish a precise dose-effect relationship between the glucose concentration and the mitochondrial transfer efficiency. Furthermore, the study only employed the STZ-induced T1DM model. Given that T2DM complicated with DKD is far more prevalent in clinical settings, this limitation may compromise the generalizability of the study findings. Although lentivirus-mediated DsRed2 labeling was utilized to achieve mitochondrial visualization, lentiviral transduction has the potential to exert subtle adverse effects on BMSCs viability and mitochondrial function.

Another study further identified mitochondrial transfer between BMSCs and glomerular endothelial cells (GECs). When GECs (pre-stimulated with 30mM glucose) were co-cultured with BMSCs, mitochondria from BMSCs were transferred to the GECs. This transfer significantly reduced the expression of IL-6, IL-1β, Caspase-3 and Bax in GECs. In vivo tail vein injection of BMSCs in diabetic rats significantly ameliorated glomerular atrophy, abnormal extracellular matrix accumulation in interstitial cells, renal interstitial fibrosis, and glomerular basement membrane thickening [43]. Regrettably, this study only confirmed the existence of the mitochondrial transfer phenomenon, without delving into the specific modalities underlying this process (e.g., TNTs and EVs). Furthermore, the researchers failed to investigate the spatial distribution of fluorescently labeled mitochondria within the renal tissues of DKD rats. Consequently, direct in vivo evidence verifying mitochondrial transfer from MSCs to GECs is lacking. Additionally, the study suffers from other limitations that compromise the credibility of its conclusions, including a small sample size in animal experiments (merely 5 rats per group) and an insufficiently representative animal model (STZ-induced T1DM rats).

Beyond PTECs and GECs, a recent study by Barutta et al. revealed that MSCs can also transfer mitochondria to damaged podocytes in DKD via TNTs. The study found that diabetes-related podocyte injury induces TNT formation between MSCs and podocytes.These TNTs facilitate the transfer of healthy mitochondria, which improves mitochondrial function in podocytes, and reduces podocyte apoptosis. In vitro experiments further demonstrated that when podocytes pretreated with high concentration of glucose (HG) were co-cultured with MSCs overexpressing M-Sec (a membrane protein that regulates TNT formation), mitochondrial transfer efficiency was significantly enhanced [94]. These findings provide new ideas for the treatment of DKD. However, the ultimate effect of mixing mtDNA from different sources in podocytes is difficult to predict. For potential clinical applications, sequencing the mtDNA of MSCs before injection to detect and quantify mtDNA variations would be a safer strategy.

Imbalanced macrophage polarization is a key immunopathological mechanism that drives DKD progression as it exacerbates renal inflammation and fibrotic damage [95–96]. Studies have shown that high glucose environment promotes the mitochondrial transfer of mouse BMSCs to RAW264.7 macrophages, thereby facilitating their polarization towards the M2 anti-inflammatory phenotype, inducing mitochondrial biogenesis in macrophages and PGC1-α/TFEB-mediated mitochondrial autophagy. This study also suggested that TNTs may mediate mitochondrial transfer from BMSCs to macrophages [97]. Future studies should measure the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and ATP production in macrophages after receiving mitochondrial components from MSCs. These measurements will help clarify whether mitochondrial transfer promotes M2 polarization by reshaping the metabolic profile of the macrophages.

Metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver disorder closely linked to insulin resistance and metabolic abnormalities, and is characterized by excessive fat accumulation in hepatocytes [98]. MASLD and diabetes mellitus exhibit a “bidirectional mutual reinforcement” relationship; they share a common underlying metabolic disturbance that mutually exacerbates each other’s pathological progression [99].

A 2021 study investigated the role of mitochondrial transfer between BMSCs and hepatocytes in diabetes-induced MASLD. This study found that when T2DM mice were injected with mitochondria-labeled BMSCs (mito-GFP) through the tail vein, their body weight significantly decreased, and the abnormal elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), and total cholesterol (TC) levels were reversed, and hepatic steatosis was completely resolved. Notably, mito-GFP fluorescence signals originating from BMSCs were detected in the liver cells. In vitro experiments further demonstrated that when HepG2 hepatocytes pretreated with a free fatty acid (FFA) mixture were co-cultured with BMSCs, lipid droplet accumulation in hepatocytes was significantly reduced [100]. Given the current lack of globally approved specific therapeutics for MASLD, the BMSCs-derived mitochondria transplantation is expected to become a feasible clinical treatment strategy for MASLD. Notably, this study used a 26-week HFD to induce T2DM mice rather than employing more convincing T2DM models such as the db/db mouse or HFD + STZ-induced T2DM model. In the in vivo experiments, the researchers did not perform colocalization analysis between hepatocyte-specific markers and mitochondrial GFP signals in liver fluorescence imaging. As a result, they could not exclude the possibility that BMSCs-derived mitochondria were transferred to non-parenchymal liver cells (e.g., macrophages, hepatic stellate cells), making it difficult to definitively confirm the target cell specificity of mitochondrial transfer in vivo.

Another study by Ruofan et al. explored how to optimize the mitochondrial transfer of MSCs in order to enhance the therapeutic effect on MASLD. The research found that when umbilical cord mesenchymal stem cells (UC-MSCs) were co-cultured with HepG2 cell mitochondria, and then these UC-MSCs were injected into the tail veins of T2DM mice, it could more effectively lower blood glucose, liver enzymes and triglyceride levels, while improving liver lipid deposition and inflammatory damage. Mechanistic studies have shown that exogenous HepG2 mitochondria can activate autophagy in UC-MSCs, promote the transfer of UC-MSCs’ mitochondria to damaged liver cells, and enhance the expression of genes related to β-oxidation in liver cells [101]. It is worth noting that the extent to which the mitochondria transferred to the liver cells originated from the UC-MSCs themselves still needs to be further confirmed. The researchers hypothesized that UC-MSC-derived mitochondria tend to be preferentially transferred to injured hepatocytes, yet they failed to investigate the underlying mechanisms governing this selective recognition. For instance, whether specific receptors are expressed on the surface of injured hepatocytes to mediate mitochondrial recognition and internalization remains to be verified by receptor-blocking assays.

Diabetic osteoporosis

Diabetic osteoporosis (DOP) is a systemic metabolic bone disorder triggered by DM and is characterized by reduced bone mineral density, impaired bone microarchitecture, decreased bone strength, increased bone fragility, significantly elevated risk of fractures, and delayed fracture healing [102]. The persistent metabolic disorder of diabetes can lead to mitochondrial dysfunction in the vascular endothelial cells and nerve cells near the bones, thereby hindering the process of local microvascular regeneration and nerve repair. Eventually, this will result in delayed bone defect healing in DOP patients with pathological fractures [103].​.

Yuxuan et al. recently identified a link between macrophage-mediated mitochondrial transfer and delayed bone defect repair in DM patients. The researchers established a full-thickness bone defect model in the HFD + STZ-induced diabetic mouse model. They found that the silicon ions released from silicified collagen scaffold (SCS) could enhance the mitochondrial oxidative phosphorylation level and Drp1-Mff-mediated mitochondrial division in RAW264.7 cells under HG stress conditions. These silicon ions also promoted the transfer of newly generated functional mitochondria from RAW264.7 cells to endothelial progenitor cells (EPCs) and PC-12 neuronal cells. This transfer subsequently enhanced the tubular formation ability of EPCs and promoted the axonal elongation of PC-12 cells. It is notable that microvesicles secreted by macrophages have been confirmed to be the key mediator in the mitochondrial transfer process [104]. These findings suggest that mitochondrial transfer may serve as a potential therapeutic target for the development of novel materials and drugs for diabetic bone-defect repair. However, this study shares the same limitation as other relevant investigations focusing on mitochondrial transfer and diabetic complications: a disconnect between the animal diabetes model and clinical practice. Specifically, this study employed an STZ-induced T1DM model, whereas DOP predominantly develops in elderly patients with T2DM. Although the study confirmed that macrophages mediate mitochondrial transfer via microvesicles, it failed to identify the specific subtype. Furthermore, the possibility of the involvement of other transfer pathways was not ruled out, making it impossible to determine whether microvesicles are the sole mediator of mitochondrial transfer.

The development of DOP is not only related to the transfer of mitochondria between macrophages and other cells but may also involve the transfer of mitochondria between osteocytes and BMSCs. MIRO1, a calcium-binding GTPase, plays a crucial role in the regulation of mitochondrial transport [105–106]. In a mouse model of glucocorticoid-induced osteoporosis, Peng et al. found that MIRO1 knockout hindered the transfer of mitochondria from osteocytes to BMSCs. This inhibitory effect makes BMSCs more likely to differentiate into osteoclasts, thereby promoting bone resorption [107]. This discovery revealed a new mechanism by which osteocytes and BMSCs regulate bone metabolic homeostasis through mitochondrial transfer. Although this study was not conducted using diabetes model, it provides new insights for exploring the pathogenesis of DOP.

Diabetes-associated cognitive dysfunction

Accumulating evidence has demonstrated that individuals with DM exhibit a 1.43- to 1.6-fold increased risk of developing cognitive impairment compared with their non-DM counterparts [108]. Neuronal mitochondrial dysfunction is a critical mediator of this association; specifically, disruption of the mitochondrial electron transport chain, combined with the accumulation of advanced glycation end products (AGEs) and impaired mitophagy, collectively leads to neuronal energy depletion. This energy deficit further exacerbates oxidative stress, which directly induces neuronal damage and apoptosis, ultimately contributing to progressive cognitive decline [109–110].

Recent research by Ma et al. revealed that mitochondrial transfer between astrocytes and neurons is closely associated with the pathogenesis of diabetes-associated cognitive dysfunction (DACD). Their findings demonstrated that phosphoserine phosphatase (PSPH) overexpression in primary db/db mouse astrocytes promotes mitochondrial transfer from astrocytes to neurons. This transfer enhanced the mitochondrial quantity and ATP synthesis capacity in neurons, mitigated neuronal nuclear condensation, and inhibited neuronal apoptosis. These results indicate that astrocytes not only provide structural support and metabolic protection to neurons but also play a crucial role in maintaining cerebral cognitive homeostasis by regulating mitochondrial transfer [111]. However, this study has a notable limitation in that it did not further validate the aforementioned mitochondrial transfer phenomenon in in vivo DACD mouse models. Furthermore, previous studies have shown that with aging and age-related decline in brain function, astrocytes transfer mitochondria to the brain capillary endothelial cells and pericytes via EVs [112]. Therefore, we should continue to explore the relationship between the onset of DACD and the phenomenon of mitochondrial transfer that occurs in other cell types besides astrocytes and neurons in the brain.

In addition to exploring the mitochondrial transfer phenomena and mechanisms in DACD, the latest research has explored an innovative therapy that aims to inhibit cuproptosis in neurons of DACD mice by transplanting mitochondrial cells from platelets. Hu et al. discovered that HFD + STZ-induced T2DM mice exhibited elevated copper levels in neurons, with downregulated expression of the proteins FDX1, LIAS and DLAT, which are related to the initiation and execution of cuproptosis. Transplantation of platelet-derived mitochondria reverses these changes and improves cognitive function in mice [113]. Future research could further investigate how exogenous mitochondria influence copper ion uptake, transport, and efflux mechanisms as well as the feedback mechanisms between mitochondrial function recovery and copper metabolism regulation.

Diabetic cardiomyopathy

Mitochondrial damage in cardiomyocytes is inevitable in the chronic pathological state of DM. The inherent self-regulation mechanisms appear insufficient to fully repair or replenish damaged mitochondria, leading to massive cardiomyocyte apoptosis and subsequent complications, such as heart failure [114–115]. Recent studies have shown that during myocardial infarction, myocardial I/R injury, heart failure, and anthracycline-induced myocardial damage (e.g., doxorubicin), various donor cell types, including MSCs, myofibroblasts, and M2 macrophages, transfer mitochondria to cardiomyocytes [116–119]. However, no correlation has been found between these mitochondrial transfer phenomena and the progression of DCM at present.

A recent study by Doulamis et al. explored the cardioprotective effects of mitochondrial transplantation in T2DM hearts with I/R injury. Zucker diabetic fatty (ZDF) rats were subjected to 30 min of thermal ischemia, followed by transplantation of mitochondria isolated from the skeletal muscles of normal Zucker lean rats. Positron emission tomography-computed tomography (PET/CT) imaging and immunohistochemical staining confirmed the effective uptake and targeted distribution of transplanted mitochondria in the myocardium of ZDF rats. Compared with the control group, the mitochondrial transplantation group exhibited significantly increased left ventricular systolic pressure, reduced left ventricular end-diastolic pressure, elevated total myocardial tissue ATP content, and decreased myocardial infarct area [120]. These findings suggest a novel therapeutic strategy for preventing I/R injury during cardiac surgery for diabetic patients. Furthermore, a separate study revealed that transferring mitochondria from normal rat cardiomyocytes to neonatal cardiomyocytes isolated from the offspring of rats with late gestational diabetes mellitus (LGDM) effectively improved cardiomyocyte bioenergetic impairment and cardiac dysfunction in LGDM offspring [121]. These studies demonstrate that targeting mitochondrial transfer in DCM holds great translational potential.

In future research, it is imperative to investigate whether intercellular mitochondrial transfer occurs in DCM, which will help fill the existing research gaps. This will help optimize the rational selection of mitochondrial donors for mitochondrial transplantation therapy, thereby improving mitochondrial dysfunction in DCM cardiomyocytes in an efficient and safe manner.

Diabetes-related male reproductive dysfunction

Dysfunction of the hypothalamic-pituitary-testicular endocrine regulatory axis in patients with diabetes can adversely affect the functions of the male reproductive system. Approximately 50% of male patients with diabetes experience varying degrees of fertility decline, with some developing infertility and erectile dysfunction [122]. A recent study investigated the effects of menstrual blood-derived endometrial stem cells (MenSCs) on male fertility and reproductive organ pathology in mouse model of T1DM. These findings revealed that tail vein injection of MenSCs significantly improved hyperglycemia in T1DM mice, enhanced insulin secretion, and upregulated the Nrf2/HO-1 pathway to restore spermatogenic cell layer thickness in testicular tissue, thereby improving sperm motility [123]. However, this study did not conclusively demonstrate whether MenSCs enhance sperm motility through mitochondrial transfer to spermatogenic cells. Given the non-invasive nature of MenSCs harvesting, this approach demonstrates significant clinical translation potential. Future research can delve deeper into whether mitochondrial transfer occurs in reproductive disorders related to diabetes and explore the underlying mechanisms.

Current challenges and controversies

Studies on mitochondrial transfer in the context of diabetes face a unique set of challenges and controversies arising from the synergistic effects of two core complexities: the inherently intricate mechanisms of mitochondrial transfer, and the multidimensional perturbations of diabetic pathological microenvironment.

Firstly, DM is accompanied by multiple pathological alterations such as hyperglycemia, insulin resistance, oxidative stress, chronic inflammation, and lipid metabolic disorders. These factors do not act in isolation but intersect and interact, exerting non-specific perturbations on the entire process of mitochondrial transfer. Secondly, we lack imaging tools capable of achieving high spatiotemporal resolution that would enable the dynamic, real-time tracking of mitochondrial transfer events within living organisms and the quantification of their actual transfer efficiency in vivo. Thirdly, it remains challenging to directly assess the functional activity of mitochondria transferred. Mitochondria isolated from the extracellular space using physical methods such as differential ultracentrifugation may undergo alterations in their structural integrity and functional status during the isolation process. Fourthly, in the in vitro co-culture of mitochondrial donor and recipient cells, it is difficult to exclude the possibility that one cell type may simultaneously regulate the function of the other through the secretion of paracrine factors. This makes it hard to establish a definitive causal link between mitochondrial transfer and the changes in the function and phenotype of recipient cells. Finally, controversies persist regarding several critical questions: whether mtDNA from donor cells can trigger the activation of innate immune-related inflammatory signaling pathways such as the cGAS-STING axis in recipient cells; whether epigenetic modifications present in exogenous mitochondria may induce metabolic disorders in recipient cells.

Conclusions and prospects

In recent years, the progressive development and extensive application of advanced research technologies, such as transgenic mice expressing mitochondrial markers (e.g., Dendra2 transgenic mice) [124], EVs extraction and purification techniques [72], EVs proteomics, and two-photon ultra-high-resolution microscopy, have facilitated the multi-dimensional investigation of mitochondrial transfer in DM and its associated complications. These studies have revealed the therapeutic effects of mitochondrial transfer [Figure 5], such as enhancing the insulin secretion function of β cells [77], improving insulin resistance [80], promoting the migration of vascular endothelial cells [84], enhancing the mitochondrial function of various renal parenchymal cells [93, 94], inhibiting liver lipid deposition [100], and repairing bone defects [104] [Tables 1 and 2]. These findings provide important insights into the intercellular communication pathogenesis of diabetes and its complications and open up potential avenues for developing mitochondrial transplantation therapies.

Fig. 5.

The specific regulatory mechanism of mitochondrial transfer in diabetes and its complications. Mesenchymal stem cells (MSCs) and other cell types can improve diabetic kidney disease, pancreatic endocrine dysfunction, MASLD, chronic diabetic wounds, cognitive dysfunction and osteoporosis, and other diabetic complications by transferring mitochondria to recipient cells to enhance mitochondrial function and regulate cellular physiological processes

Table 1.

Summary of research on mitochondrial transfer in diabetes, chronic diabetic wounds and diabetic kidney disease

Disease	Year	animal model	Donor cell	Receptor cell	Mitochondrial status	Transfer mechanism	Transfer outcome	Ref
T1DM	2019	Not used	①Human adipose-derived MSCs; ②Mouse adipose-derived MSCs;	①Human pancreatic islet β cells; ②Mouse pancreatic islet β cells	Healthy mitochondria	EVs and TNTs	Enhanced insulin secretion stimulated by glucose and mitochondrial respiratory capacity	[77]
T2DM	2024	C57BL/6 mice fed with HFD	Primary astrocyte cells of mice	POMC neuronal cells	Healthy mitochondria	Not identified	Enhanced the neurons’ sensitivity to glucose	[80]
Chronic diabetic wounds	2025	T2DM SD rats induced by HFD + STZ	M2 macrophages derived from THP−1 cells	HUVECs	Healthy mitochondria	Not identified	Repaired the mitochondrial structure and function, promoted the expression of MMP9, VEGFR and TIE2, and enhanced the cell migration ability.	[84]
	2025	T1DM SD rats induced by STZ	M2 macrophages derived from RAW264.7 cells	HUVECs	Healthy mitochondria	EVs	Enhanced the tubular formation and migration ability, reduced ROS production, and increased mitochondrial membrane potential	[85]
	2024	Diabetic foot ulcers (DFU) mice induced by STZ	Human-derived UC-MSCs	Neutrophils isolated from the bone marrow of mice	Healthy mitochondria	EVs	Reduced neutrophil ferroptosis and NETs formation, enhanced mitochondrial membrane potential and oxidative phosphorylation function.	[89]
Diabetic kidney disease	2019	①T1DM C57BL/6 mice induced by STZ; ②T1DM SD rats induced by STZ	SD Rat-derived BMSCs	①Primary PTECs of T1DM rats; ②NRK−52E cells	Healthy mitochondria	Not identified	Enhance the colony-forming ability, improve nuclear degeneration and atrophy, promote the expression of SOD2, Bcl−2, Megalin and SGLT2, reduce ROS production, and inhibit cell apoptosis	[93]
	2022	T1DM SD rats induced by STZ	SD Rat-derived BMSCs	GECs	Healthy mitochondria	Not identified	Reduced apoptosis, increased the expressions of SOD2, DRP1 and MFN2, increased the mitochondrial membrane potential.	[43]
	2024	T1DM C57BL/6 mice induced by STZ	①Human-derived MSCs; ②Mouse-derived BMSCs	①Conditional immortalized podocytes; ②Primary mouse podocytes	Healthy mitochondria	TNTs	Improve the mitochondrial function of podocytes, reduce cell apoptosis, decrease the infiltration of renal glomerular macrophages in diabetic mice, and promote the expression of TFAM, COX1 and ND4L.	[94]
	2021	T1DM C57BL/6 mice induced by STZ	①Mouse-derived BM-MSCs; ②RAW264.7 cells	Macrophages in the peritoneum and kidneys of mice	Healthy mitochondria	TNTs	Improved mitochondrial respiratory function, promoted M2 polarization and mitochondrial autophagy, reduced the expression of IL−1β and TNF-α, and alleviate renal fibrosis	[97]

Table 2.

Summary of research on mitochondrial transfer in MASLD, diabetic osteoporosis, and diabetes-associated cognitive dysfunction

Disease	Year	animal model	Donor cell	Receptor cell	Mitochondrial status	Transfer mechanism	Transfer outcome	Ref
Metabolic dysfunction- associated steatotic liver disease	2021	T2DM C57BL/6 mice induced by HFD	Mouse-derived BMSCs	①HepG2 cells exposed to OA and PA; ②Primary liver cells of HFD mice	Healthy mitochondria	Not identified	Improved intracellular lipid accumulation and mitochondrial dysfunction, reduced ROS production, and promoted the expression of AKT, VDAC1 and HO1.	[100]
	2025	T2DM C57BL/6 mice induced by HFD + STZ	Human-derived UC-MSCs	Liver cells of T2DM mice	Healthy mitochondria	Not identified	Promoted the expression of β-oxidation-related genes such as PPARα and ACOX1, reduced lipid accumulation in cells, alleviated liver inflammation and serum levels of ALT and AST.	[101]
Diabetic osteoporosis	2024	T1DM C57BL/6 mice induced by STZ	RAW264.7 cells	①EPCs cells; ②PC−12 cells	Healthy mitochondria	EVs	Enhanced the tubular formation ability of EPCs, promoted the axonal elongation of PC−12 cells.	[104]
Diabetes-associated cognitive dysfunction	2023	db/db mice	Primary astrocytes of mice	Primary neurons of mice	Healthy mitochondria	Not identified	Increased the number of mitochondria in neurons and enhanced their ATP synthesis capacity, alleviated the phenomenon of neuronal nuclear condensation, and inhibited neuronal apoptosis.	[111]

While our understanding of mitochondrial transfer events in DM and its complications has gradually deepened, these exploratory studies remain in their infancy and are plagued by numerous methodological flaws. For examples, the use of T1DM animal models to investigate chronic complications, the application of mitochondrial fluorescent dyes prone to generating false-positive results, the lack of in vivo validation for mitochondrial transfer events, and insufficient exploration of the underlying mechanisms. Furthermore, the scope of existing research is also restricted. For instance, current studies have exclusively focused on the transfer of healthy mitochondria, whereas the potential role of intercellular transfer of damaged mitochondria in diabetes-related complications has not received adequate attention. Investigations into other potential mitochondrial donor cell types, such as mesenchymal stem cells derived from induced pluripotent stem cells (iPSC-MSCs), remain relatively scarce. Additional research is urgently needed to explore whether alternative mechanisms of mitochondrial transfer exist beyond EVs, TNTs, gap junctions, and the transfer of free mitochondria, as well as to elucidate the synergistic or competitive relationships between these different transfer pathways. In addition, a growing number of plant extracts have been reported to possess antioxidant and anti-inflammatory potential, such as those from myrtle fruit, Glycyrrhiza glabra L., and Origanum species [125–127]. Thus, investigating whether these natural compounds can ameliorate mitochondrial dysfunction in target tissues and organs caused by oxidative stress and inflammation microenvironment in DM, and further exploring their potential to modulate the mitochondrial transfer process, should also be identified as one of the major research directions for the future.

In summary, despite persistent limitations in study design and scope within the field of mitochondrial transfer research, we firmly believe that a combination of initiatives—including advancing fundamental research, enhancing experimental rigor, expanding the research scope, and developing more sophisticated detection technologies for mitochondrial transfer—will collectively drive a comprehensive understanding of the regulatory networks governing mitochondrial transfer in DM and its complications. Such groundbreaking progress will accelerate the development of therapeutic agents targeting mitochondrial transfer, thereby providing more precise and effective strategies for ameliorating DM and its associated complications.

Abbreviations

AD-MSCs

Adipose-derived mesenchymal stem cells

AGEs

Advanced glycation end products

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

ATP

Adenosine triphosphate

BMSCs

Bone marrow mesenchymal stem cells

CNS

Central nervous system

COS

Chitosan oligosaccharide

CX43

Connexin 43

DACD

Diabetes-associated cognitive dysfunction

DCM

Diabetic cardiomyopathy

DKD

Diabetic kidney disease

DM

Diabetes mellitus

DOP

Diabetic osteoporosis

ECAR

Extracellular acidification rate

EPCs

Endothelial progenitor cells

ER

Endoplasmic reticulum

EVs

Extracellular vesicles

FFA

Free fatty acid

GECs

Glomerular endothelial cells

HG

High concentration of glucose

HFD

High-fat diet

HUVECs

Human umbilical vein endothelial cells

IDF

International Diabetes Federation

I/R

Ischemia-reperfusion

iPSCs

Induced pluripotent stem cells

LGDM

Late gestational diabetes mellitus

MASLD

Metabolic dysfunction-associated steatotic liver disease

MBH

Mediobasal hypothalamus

MenSCs

Menstrual blood-derived endometrial stem cells

Mito-EVs

Mitochondrial-related extracellular vesicles

mito-GFP

Mitochondrial GFP

MQC

Mitochondrial quality control

MSC-EVs

Extracellular vesicles derived from mesenchymal stem cells

MSCs

Mesenchymal stem cells

mtDNA

Mitochondrial DNA

MVBs

Multivesicular bodies

NETs

Neutrophil extracellular traps

NTA

Nanoparticle tracking analysis

POMC

Pro-opiomelanocortin

PA

Palmitic acid

PTECs

Proximal tubule epithelial cells

PSPH

Phosphoserine phosphatase

PET/CT

Positron emission tomography-computed tomography

ROS

Reactive oxygen species

SCS

Silicified collagen scaffold

STZ

Streptozotocin

TC

Total cholesterol

T1DM

Type 1 diabetes mellitus

T2DM

Type 2 diabetes mellitus

TG

Triglycerides

TEM

Transmission electron microscopy

TNTs

Tunneling nanotubes

UC-MSCs

Umbilical cord mesenchymal stem cells

ZDF

Zucker diabetic fatty

Authors’ contributions

DL, XL and LZ designed and outlined the manuscript. All authors contributed to the literature search and drafted and revised the manuscript.

Funding

This work was supported by the Natural Science Foundation of China (No.U22A20286, No.82470854, No.82170834, No.U22A20286, No.82470854), National Science and Technology Major Project (No.2024ZD0531901), Noncommunicable Chronic Diseases-National Scienceand Technology Major Project (No.2024ZD0531300), China International medical foundation (No. Z-2017-26-2202-4), Sichuan Science and Technology Program (No.2024YFFK0081), Health Commission of Sichuan Province Medical Science and Technology Program (No.24CXTD02), Clinical Medicine Special Project of Southwest Medical University (No.2024LCYXZX12), and the Scientific Research Project of Southwest Medical University (No.2024LCYXZX02).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors approved the final manuscript for publication.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.