Mitochondrial Quality Control System Research Articles

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1β-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA-PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA-PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity.

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.

Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

Renal aging and mitochondrial quality control.

Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems.

Depression is the most disabling neuropsychiatric disorder, causing difficulties in daily life activities and social interactions. The exact mechanisms of depression remain largely unclear. However, some studies have shown that mitochondrial dysfunction would play a crucial role in the occurrence and development of depression. To summarize the known knowledge about the role of mitochondrial dysfunction in the pathogenesis of depression. We review the recent literature， including 105 articles, to summarize the mitochondrial energy metabolism and quality control systems in the occurrence and development of depression. Some antidepressants which may exert their effects by improving mitochondrial function are also discussed. Impaired brain energy metabolism and (or) damaged mitochondrial quality control systems have been reported not only in depression patients but in animal models of depression. Although the classical antidepressants have not been specially designed to target mitochondria, the evidence suggests that many antidepressants may exert their effects by improving mitochondrial function. This brief review focuses on the findings that implicate mitochondrial dysfunction and the quality control systems as important etiological factors in the context of depressive disorders. It will help us to understand the various concepts of mitochondrial dysfunction in the pathogenesis of depression, and to explore novel and more targeted therapeutic approaches for depression.

Maintaining the Mitochondrial Quality Control System Was a Key Event of Tanshinone IIA against Deoxynivalenol-Induced Intestinal Toxicity.

Deoxynivalenol (DON) is the one of the most common mycotoxins, widely detected in various original foods and processed foods. Tanshinone IIA (Tan IIA) is a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza Bunge, which has multi-biological functions and pharmacological effects. However, whether Tan IIA has a protective effect against DON-induced intestinal toxicity is unknown. In this study, the results showed Tan IIA treatment could attenuate DON-induced IPEC-J2 cell death. DON increased oxidation product accumulation, decreased antioxidant ability and disrupted barrier function, while Tan IIA reversed DON-induced barrier function impairment and oxidative stress. Furthermore, Tan IIA dramatically improved mitochondrial function via mitochondrial quality control. Tan IIA could upregulate mitochondrial biogenesis and mitochondrial fusion as well as downregulate mitochondrial fission and mitochondrial unfolded protein response. In addition, Tan IIA significantly attenuated mitophagy caused by DON. Collectively, Tan IIA presented a potential protective effect against DON toxicity and the underlying mechanisms were involved in mitochondrial quality control-mediated mitophagy.

Impact of Mitochondrial Architecture, Function, Redox Homeostasis, and Quality Control on Organismic Aging: Lessons from a Fungal Model System.

Significance: Mitochondria are eukaryotic organelles with various essential functions. They are both the source and the targets of reactive oxygen species (ROS). Different branches of a mitochondrial quality control system (mQCS), such as ROS balancing, degradation of damaged proteins, or whole mitochondria, can mitigate the adverse effects of ROS stress. However, the capacity of mQCS is limited. Overwhelming this capacity leads to dysfunctions and aging. Strategies to interfere into mitochondria-dependent human aging with the aim to increase the healthy period of life, the health span, rely on the precise knowledge of mitochondrial functions. Experimental models such as Podospora anserina, a filamentous fungus with a clear mitochondrial aging etiology, proved to be instrumental to reach this goal. Recent Advances: Investigations of the P. anserina mQCS revealed that it is constituted by a complex network of different branches. Moreover, mitochondrial architecture and lipid homeostasis emerged to affect aging. Critical Issues: The regulation of the mQCS is only incompletely understood. Details about the involved signaling molecules and interacting pathways remain to be elucidated. Moreover, most of the currently generated experimental data were generated in well-controlled experiments that do not reflect the constantly changing natural life conditions and bear the danger to miss relevant aspects leading to incorrect conclusions. Future Directions: In P. anserina, the precise impact of redox signaling as well as of molecular damaging for aging remains to be defined. Moreover, natural fluctuation of environmental conditions needs to be considered to generate a realistic picture of aging mechanisms as they developed during evolution.

Mitochondria in Multi-Directional Differentiation of Dental-Derived Mesenchymal Stem Cells.

The pursuit of tissue regeneration has fueled decades of research in regenerative medicine. Among the numerous types of mesenchymal stem cells (MSCs), dental-derived mesenchymal stem cells (DMSCs) have recently emerged as a particularly promising candidate for tissue repair and regeneration. In recent years, evidence has highlighted the pivotal role of mitochondria in directing and orchestrating the differentiation processes of DMSCs. Beyond mitochondrial energy metabolism, the multifaceted functions of mitochondria are governed by the mitochondrial quality control (MQC) system, encompassing biogenesis, autophagy, and dynamics. Notably, mitochondrial energy metabolism not only governs the decision to differentiate but also exerts a substantial influence on the determination of differentiation directions. Furthermore, the MQC system exerts a nuanced impact on the differentiation of DMSCs by finely regulating the quality and mass of mitochondria. The review aims to provide a comprehensive overview of the regulatory mechanisms governing the multi-directional differentiation of DMSCs, mediated by both mitochondrial energy metabolism and the MQC system. We also focus on a new idea based on the analysis of data from many research groups never considered before, namely, DMSC-based regenerative medicine applications.

Cardiomyocyte-specific beta3-adrenergic receptor expression reduces infarct size inhibiting the autophagic flux in mice

Abstract Background Since the discovery of β3-adrenergic receptor (β3AR), the third class of β-adrenergic receptors, expression in in both cardiomyocytes and endothelial cells of the cardiovascular system, it has come to the focus due to it´s possible implication in cardiovascular diseases. Although it´s expression is low compared to β1 and β2 subtypes (1), its been demonstrated that β3AR agonists have a cardioprotective effect in ischemia/reperfusion (IR) injury though inhibition of mitochondrial pore opening (2). Purpose In this project we determined the cellular origin of the β3AR cardioprotection and its role on cellular autophagic machinery. Methods Mice with overexpression of the β3AR in cardiomyocytes or endothelial cells and their control littermates were subjected to left coronary artery occlusion for 45 min followed reperfusion after 24h and 7days. Left ventricular function was assessed by echocardiography at day 7. Then, heart samples were collected at baseline and 24h and 7 days after IRI. Mitochondrial number were analyzed by transmission electron microscopy. Proteins related to autophagy signaling pathways were measured by western blot and RT-qPCR. Results Cardiomyocyte-specific β3AR overexpression protects the heart upon IR injury, reduced cardiac fibrosis which improved cardiac function and maintained heart mass. Studying the effects at baseline to understand the molecular mechanisms of cardioprotection, we found that β3AR overexpression in cardiomyocytes showed a reduction in autophagy markers such as LC3B and Parkin, meaning there is an alteration in the autophagic flux. Conclusions Cardiomyocyte-specific overexpression of β3-adrenergic receptor reduces infarct size and protects the heart affecting the autophagy machinery. Our results shed light on the role of the β3AR in the mitochondrial quality control system, offering evidence of its potential use as a target to decrease IR injury in patients with acute myocardial infarction.

Cardiac fibroblasts-mtExosomes-macrophages axis aggravates ventricular remodeling after acute myocardial infarction

Abstract Background Intercellular communication between cardiac fibroblasts (CFs) and macrophages plays an important role in the progression of ventricular remodeling after acute myocardial infarction (AMI). Following intense oxidative stress, activation of mitochondrial quality control (MQC) systems is necessary to eliminate damaged components. Recent studies have highlighted the emergence of a new form of MQC called mitochondrial-derived vesicles (MDVs), which can be released into the extracellular space via exosomes. Our previous research has revealed that exosomes derived from fibroblasts treated with oxygen-glucose deprivation (OGD) contained mitochondrial damage components, which we named "mtExosomes". The uptake of mtExosomes by macrophages can significantly promote inflammatory response. Purpose To explore the specific effects of CFs-mtExosomes-macrophages communication axis on ventricular remodeling after AMI. Methods Male C57 mice underwent left anterior descending coronary artery-ligation surgery for orthotopic myocardial injection of CFs derived exosomes. Primary neonatal mouse CFs were isolated and cultured for 24h in sugar-free medium with 1% O2 (OGD) to mimic ischemic injury in vitro. Conditioned medium was separated to obtain exosomes by ultracentrifugation. Label-free quantitative proteomics was used to identify differentially expressed proteins in exosomes. The damaged mitochondrial components in the exosomes were identified using mito-tracker and nanoflowmetry. After co-culture with OGD-CFs derived exosomes for 24h, RNA-seq was performed to analyze the activated inflammatory signaling pathways in bone marrow-derived macrophages. Results OGD-CFs derived exosomes significantly reduced cardiac function post-surgery day 3 in model mice, and fibrotic remodeling was observed at 28 days. In vitro co-culture experiments revealed that the conditioned medium from OGD-CFs increased the expression and secretion of IL-1β and IL-6 in macrophages. Separation of secretory components by differential centrifugation suggested that exosomes had the most significant pro-inflammatory effect on macrophages. Exosome proteomics showed that fibroblast-derived exosomes were rich in mitochondrial proteins. A significant fluorescence signal was detected by nanoflowmetry after incubation of OGD-CFs-derived exosomes with Mito-tracker. OGD-CFs derived exosomes also had higher mtDNA, mtROS, and ATP levels. RNA-seq enrichment analysis revealed significant activation of Toll-like receptor and NOD-like receptor signaling pathways in macrophages. Western blot analysis further confirmed the up-regulation of NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways. Conclusion Following ischemic injury, CFs in infarction area release exosomes rich in damaged mitochondria (mtExosomes). The uptake of mtExosomes by macrophages promotes the secretion of IL-6 and IL-1β via NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways, leading to ventricular remodeling after AMI.Graphical Abstract

Mitochondrial transfer between cell crosstalk - An emerging role in mitochondrial quality control.

Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of such cellular component exchange. In physiological situations, mitochondrial transfer is linked with biological development, energy coordination, and clearance of harmful components, remarkably playing important roles in maintaining mitochondrial quality. Mitochondria are engaged in many critical biological activities, like oxidative metabolism and biomolecular synthesis, and are exclusively prone to malfunction in pathological processes. Importantly, severe mitochondrial damage will further amplify the defects in the mitochondrial quality control system, which will mobilize more active mitochondrial transfer, replenish exogenous healthy mitochondria, and remove endogenous damaged mitochondria to facilitate disease outcomes. This review explores intercellular mitochondrial transport in cells, its role in cellular mitochondrial quality control, and the linking mechanisms in cellular crosstalk. We also describe advances in therapeutic strategies for diseases that target mitochondrial transfer.

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

The Role of Parkin in Rat Pancreatic Beta Cells Fate.

Parkin is a member of the mitochondrial quality control system that plays a major role in mitophagy. Although the loss of function mutations in the Parkin gene has been associated with the Familial Parkinson's phenotype, research in recent years points out that Parkin's function is not limited to neurodegenerative diseases. Parkin's function impressing key cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, makes it an important player in the maintenance of cellular homeostasis. In this study, we investigated whether Parkin affects cell viability and ER stress responses under lipotoxic conditions in INS-1E cells. Our results may suggest that silencing Parkin may affect autophagy in addition to apoptosis. We also showed that Parkin may have a protective effect against lipo-toxic effects in INS-1E cells. Consistent with previous studies, we observed that stress responses were different for high and low palmitic acid doses. The Parkin being inhibited under high-dose PA treatment and active under low-dose PA treatment indicate that regulation of stress responses is controlled by environmental conditions. Our preliminary findings may suggest that in low lipotoxic conditions, Parkin affects the ER stress response by modulating Chop activity and Ca2+ release from the ER to the cytoplasm.

Changes in the Mitochondria in the Aging Process-Can α-Tocopherol Affect Them?

Aerobic organisms use molecular oxygen in several reactions, including those in which the oxidation of substrate molecules is coupled to oxygen reduction to produce large amounts of metabolic energy. The utilization of oxygen is associated with the production of ROS, which can damage biological macromolecules but also act as signaling molecules, regulating numerous cellular processes. Mitochondria are the cellular sites where most of the metabolic energy is produced and perform numerous physiological functions by acting as regulatory hubs of cellular metabolism. They retain the remnants of their bacterial ancestors, including an independent genome that encodes part of their protein equipment; they have an accurate quality control system; and control of cellular functions also depends on communication with the nucleus. During aging, mitochondria can undergo dysfunctions, some of which are mediated by ROS. In this review, after a description of how aging affects the mitochondrial quality and quality control system and the involvement of mitochondria in inflammation, we report information on how vitamin E, the main fat-soluble antioxidant, can protect mitochondria from age-related changes. The information in this regard is scarce and limited to some tissues and some aspects of mitochondrial alterations in aging. Improving knowledge of the effects of vitamin E on aging is essential to defining an optimal strategy for healthy aging.

Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.

Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.

Post-translational modifications and protein quality control of mitochondrial channels and transporters.

Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.

Multifaceted mitochondrial quality control in brown adipose tissue.

Brown adipose tissue (BAT) controls mammalian core body temperature by non-shivering thermogenesis. BAT is extraordinarily rich in mitochondria, which have the peculiarity of generating heat by uncoupled respiration. Since the mitochondrial activity of BAT is subject to cycles of activation and deactivation in response to environmental temperature changes, an integrated mitochondrial quality control (MQC) system is of fundamental importance to ensure BAT physiology. Here, we provide an overview of the conventional and alternative mechanisms through which thermogenic adipocytes selectively remove damaged parts of mitochondria and how macrophages participate in the MQC system by removing extracellular mitochondrial waste to maintain the thermogenic function of BAT.

FUNDC1: An Emerging Mitochondrial and MAMs Protein for Mitochondrial Quality Control in Heart Diseases.

Heart diseases (HDs) are the leading cause of mortality worldwide, with mitochondrial dysfunction being a significant factor in their development. The recently discovered mitophagy receptor, FUNDC1, plays a critical role in regulating the homeostasis of the Mitochondrial Quality Control (MQC) system and contributing to HDs. The phosphorylation of specific regions of FUNDC1 and varying levels of its expression have been shown to have diverse effects on cardiac injury. This review presents a comprehensive consolidation and summary of the latest evidence regarding the role of FUNDC1 in the MQC system. The review elucidates the association of FUNDC1 with prevalent HDs, such as metabolic cardiomyopathy (MCM), cardiac remodeling/heart failure, and myocardial ischemia-reperfusion (IR) injury. The results indicate that the expression of FUNDC1 is elevated in MCM but reduced in instances of cardiac remodeling, heart failure, and myocardial IR injury, with divergent impacts on mitochondrial function among distinct HDs. Exercise has been identified as a powerful preventive and therapeutic approach for managing HDs. Additionally, it has been suggested that exercise-induced enhancement of cardiac function may be attributed to the AMPK/FUNDC1 pathway.

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.

The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.

MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.