Role Of Mitochondrial Dysfunction Research Articles

Parkinson’s Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA

Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in Parkinson's disease (PD) pathophysiology. This paper aims to review the latest literature published, focusing on genetic defects and expression alterations affecting mitochondria-associated genes, in support of their key role in PD pathogenesis. Thanks to the use of new omics approaches, a growing number of studies are discovering alterations affecting genes with mitochondrial functions in patients with PD and parkinsonisms. These genetic alterations include pathogenic single-nucleotide variants, polymorphisms acting as risk factors, and transcriptome modifications, affecting both nuclear and mitochondrial genes. We will focus on alterations of mitochondria-associated genes described by studies conducted on patients or on animal/cellular models of PD or parkinsonisms. We will comment how these findings can be taken into consideration for improving the diagnostic procedures or for deepening our knowledge on the role of mitochondrial dysfunctions in PD.

VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis

Mitochondrial dysfunction was shown to be involved in schizophrenia pathophysiology. Abnormal energy states can lead to alterations in neural function and thereby to the cognitive and behavioral aberrations characteristics of schizophrenia. Voltage-dependent anion-selective channels (VDAC) are located in the outer mitochondrial membrane and are involved in mitochondrial energy production. Only few studies explored VDAC genes’ expression in schizophrenia, and their results were not consistent. We conducted a systematic meta-analysis of ten brain samples gene expression datasets (overall 368 samples, 179 schizophrenia, 189 controls). In addition, we conducted a meta-analysis of three blood samples datasets (overall 300 samples, 167 schizophrenia, 133 controls). Pairwise correlation analysis was conducted between the VDAC and proteasome subunit genes’ expression patterns. VDAC1, VDAC2 and VDAC3 showed significant down-regulation in brain samples of patients with schizophrenia. They also showed significant positive correlations with the proteasome subunit genes’ expression levels. Our findings suggest that VDAC genes might play a role in mitochondrial dysfunction in schizophrenia. VDAC1 was down-regulated also in blood samples, which suggests its potential role as a biomarker for schizophrenia. The correlation with proteasome subunits, which were previously shown to be down-regulated in a subgroup of the patients, suggests that our findings might characterize a subgroup of the patients. This direction has the potential to lead to patients’ stratification and more precisely-targeted therapy and necessitates further study.

RUNX1 Upregulation Causes Mitochondrial Dysfunction via Regulating the PI3K-Akt Pathway in iPSC from Patients with Down Syndrome.

Down syndrome (DS) is the most common autosomal aneuploidy caused by trisomy of chromosome 21. Previous studies demonstrated that DS affected mitochondrial functions, which may be associated with the abnormal development of the nervous system in patients with DS. Runt-related transcription factor 1 (RUNX1) is an encoding gene located on chromosome 21. It has been reported that RUNX1 may affect cell apoptosis via the mitochondrial pathway. The present study investigated whether RUNX1 plays a critical role in mitochondrial dysfunction in DS and explored the mechanism by which RUNX1 affects mitochondrial functions. Expression of RUNX1 was detected in induced pluripotent stem cells of patients with DS (DS-iPSCs) and normal iPSCs (N-iPSCs), and the mitochondrial functions were investigated in the current study. Subsequently, RUNX1 was overexpressed in N-iPSCs and inhibited in DS-iPSCs. The mitochondrial functions were investigated thoroughly, including reactive oxygen species levels, mitochondrial membrane potential, ATP content and lysosomal activity. Finally, RNA-sequencing was used to explore the global expression pattern. It was observed that the expression levels of RUNX1 in DS-iPSCs were significantly higher than those in normal controls. Impaired mitochondrial functions were observed in DS-iPSCs. Of note, overexpression of RUNX1 in N-iPSCs resulted in mitochondrial dysfunction, while inhibition of RUNX1 expression could improve the mitochondrial function in DS-iPSCs. Global gene expression analysis indicated that overexpression of RUNX1 may promote the induction of apoptosis in DS-iPSCs by activating the PI3K/Akt signaling pathway. The present findings indicate that abnormal expression of RUNX1 may play a critical role in mitochondrial dysfunction in DS-iPSCs.

Linc279227 contributes to mitochondrial dysfunction in high glucose-treated mouse renal tubular epithelial cells

BackgroundThe aberrant expression of long noncoding RNAs (lncRNAs) has been associated with diabetic nephropathy (DN), a major complication of diabetes mellitus (DM). This study investigated the differential expression of lncRNAs in DM without renal damage and DM with renal damage, known as DN, and elucidated the functions of a pathogenic lncRNA. MethodsHigh-throughput sequencing was performed on the kidneys of male db/db mice with kidney injury, db/db mice without kidney involvement and db/m control littermates. Linc279227 expression was confirmed by RT‒qPCR and fluorescence in situ hybridization. The effects of linc279227 on high glucose (HG)-treated renal tubular epithelial cells (RTECs) were evaluated by autophagy flux monitoring, Western blot determination and mitochondrial morphological detection. ResultsWith high-throughput sequencing, we identified a 1024 nt long intergenic noncoding RNA, TCONS_00279227 (linc279227), whose expression was markedly increased in the kidneys of db/db mice with kidney injury compared to db/db mice without kidney injury and db/m control littermates. Fluorescence in situ hybridization confirmed that linc279227 was mainly located in the renal tubules of mice with DN. In vitro, linc279227 expression was found to be significantly increased in RTECs treated with high glucose (HG) for 48 h. Silencing linc279227 markedly restored the levels of autophagy-/mitophagy-associated proteins in HG-stimulated RTECs. Furthermore, silencing linc279227 reduced phosphorylated Drp1 expression and increased Mfn2 expression in RTECs exposed to HG. ConclusionOur data suggest that linc279227 plays an important role in mitochondrial dysfunction in HG-treated RTECs and that silencing linc279227 rescues RTECs exposed to HG.

Mitochondrial DNA Mutations and Ageing.

Mitochondria are subcellular organelles present in most eukaryotic cells which play a significant role in numerous aspects of cell biology. These include carbohydrate and fatty acid metabolism to generate cellular energy through oxidative phosphorylation, apoptosis, cell signalling, haem biosynthesis and reactive oxygen species production. Mitochondrial dysfunction is a feature of many human ageing tissues, and since the discovery that mitochondrial DNA mutations were a major underlying cause of changes in oxidative phosphorylation capacity, it has been proposed that they have a role in human ageing. However, there is still much debate on whether mitochondrial DNA mutations play a causal role in ageing or are simply a consequence of the ageing process. This chapter describes the structure of mammalian mitochondria, and the unique features of mitochondrial genetics, and reviews the current evidence surrounding the role of mitochondrial DNA mutations in the ageing process. It then focusses on more recent discoveries regarding the role of mitochondrial dysfunction in stem cell ageing and age-related inflammation.

The Role of Mitochondria in Cartilage Degenerative Disorders

Mitochondria are major organelles that produce energy for cellular metabolism and are vital to proper cell functioning. Metabolic dysregulation is a critical contributing factor to the initiation and development of degenerative and autoimmune diseases, thus is present in cartilage disorders such as osteoarthritis and rheumatoid arthritis. Mitochondrial dysfunction in cartilage diseases is especially interesting because it may present a promising therapeutic and anti-ageing target. By understanding the mechanism of mitochondrial dysfunction, we can aim to upregulate the role of mitochondria in treating cartilage diseases. In this review, we look at the role of mitochondrial dysfunction in degenerative cartilage diseases and mitochondria as tools in the treatment of osteoarthritis and rheumatoid arthritis.

Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury

Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following a moderate contusive SCI at the 10th thoracic (T10) level. Cellular, molecular, and genetic assessments were performed to determine whether CL alterations mediate mitochondrial dysfunction and neuronal death after SCI, and, if so, whether reversing CL alteration leads to neuroprotection after SCI. Using lipidomic analysis, we uncovered CL alterations at an early stage of SCI. Over 50 distinct CL species were identified, of which 50% showed significantly decreased abundance after SCI. The decreased CL species contained mainly polyunsaturated fatty acids that are highly susceptible to peroxidation. In parallel, 4-HNE, a lipid peroxidation marker, significantly increased after SCI. We found that mitochondrial oxidative stress not only induced CL oxidation, but also resulted in CL loss by activating cPLA2 to hydrolyze CL. CL alterations induced mitochondrial dysfunction and neuronal death. Remarkably, pharmacologic inhibition of CL alterations with XJB-5-131, a novel mitochondria-targeted electron and reactive oxygen species scavenger, reduced cell death, tissue damage and ameliorated motor deficits after SCI in adult rats. These findings suggest that CL alteration could be a novel mechanism that mediates injury-induced neuronal death, and a potential therapeutic target for ameliorating secondary SCI.

Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases

Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson-Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.

Role of Oxidative Stress and Inflammation in Insomnia Sleep Disorder and Cardiovascular Diseases: Herbal Antioxidants and Anti-inflammatory Coupled with Insomnia Detection using Machine Learning.

Insomnia is well-known as trouble in sleeping and enormously influences human life due to the shortage of sleep. Reactive Oxygen Species (ROS) accrue in neurons during the waking state, and sleep has a defensive role against oxidative damage and dissipates ROS in the brain. In contrast, insomnia is the source of inequity between ROS generation and removal by an endogenous antioxidant defense system. The relationship between insomnia, depression, and anxiety disorders damages the cardiovascular systems' immune mechanisms and functions. Traditionally, polysomnography is used in the diagnosis of insomnia. This technique is complex, with a long time overhead. In this work, we have proposed a novel machine learning-based automatic detection system using the R-R intervals extracted from a single-lead electrocardiograph (ECG). Additionally, we aimed to explore the role of oxidative stress and inflammation in sleeping disorders and cardiovascular diseases, antioxidants' effects, and the psychopharmacological effect of herbal medicine. This work has been carried out in steps, which include collecting the ECG signal for normal and insomnia subjects, analyzing the signal, and finally, automatic classification. We used two approaches, including subjects (normal and insomnia), two sleep stages, i.e., wake and rapid eye movement, and three Machine Learning (ML)-based classifiers to complete the classification. A total number of 3000 ECG segments were collected from 18 subjects. Furthermore, using the theranostics approach, the role of mitochondrial dysfunction causing oxidative stress and inflammatory response in insomnia and cardiovascular diseases was explored. The data from various databases on the mechanism of action of different herbal medicines in insomnia and cardiovascular diseases with antioxidant and antidepressant activities were also retrieved. Random Forest (RF) classifier has shown the highest accuracy (subjects: 87.10% and sleep stage: 88.30%) compared to the Decision Tree (DT) and Support Vector Machine (SVM). The results revealed that the suggested method could perform well in classifying the subjects and sleep stages. Additionally, a random forest machine learning-based classifier could be helpful in the clinical discovery of sleep complications, including insomnia. The evidence retrieved from the databases showed that herbal medicine contains numerous phytochemical bioactives and has multimodal cellular mechanisms of action, viz., antioxidant, anti-inflammatory, vasorelaxant, detoxifier, antidepressant, anxiolytic, and cell-rejuvenator properties. Other herbal medicines have a GABA-A receptor agonist effect. Hence, we recommend that the theranostics approach has potential and can be adopted for future research to improve the quality of life of humans.

Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress.

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.

Significance of Mitochondrial Dysfunction in the Progression of Multiple Sclerosis.

The prevalence of multiple sclerosis and the complexity of its etiology and pathogenesis require further study of the factors underlying the progression of this disease. The prominent role of mitochondria in neurons makes this organelle a vulnerable target for CNS diseases. The purpose of this review is to consider the role of mitochondrial dysfunction in the pathogenesis of multiple sclerosis, as well as to propose new promising therapeutic strategies aimed at restoring mitochondrial function in multiple sclerosis.

Mitochondrial dysfunction in heart failure and its therapeutic implications.

The ATP consumption in heart is very intensive to support muscle contraction and relaxation. Mitochondrion is the power plant of the cell. Mitochondrial dysfunction has long been believed as the primary mechanism responsible for the inability of energy generation and utilization in heart failure. In addition, emerging evidence has demonstrated that mitochondrial dysfunction also contributes to calcium dysregulation, oxidative stress, proteotoxic insults and cardiomyocyte death. These elements interact with each other to form a vicious circle in failing heart. The role of mitochondrial dysfunction in the pathogenesis of heart failure has attracted increasing attention. The complex signaling of mitochondrial quality control provides multiple targets for maintaining mitochondrial function. Design of therapeutic strategies targeting mitochondrial dysfunction holds promise for the prevention and treatment of heart failure.

Immune senescence in multiple myeloma-a role for mitochondrial dysfunction?

Age-related immune dysfunction is primarily mediated by immunosenescence which results in ineffective clearance of infective pathogens, poor vaccine responses and increased susceptibility to multi-morbidities. Immunosenescence-related immunometabolic abnormalities are associated with accelerated aging, an inflammatory immune response (inflammaging) and ultimately frailty syndromes. In addition, several conditions can accelerate the development of immunosenescence, including cancer. This is a bi-directional interaction since inflammaging may create a permissive environment for tumour development. Multiple myeloma (MM) is a mature B-cell malignancy that presents in the older population. MM exemplifies the interaction of age- (Host Response Biology; HRB) and disease-related immunological dysfunction, contributing to the development of a frailty syndrome which impairs the therapeutic impact of recent advances in treatment strategies. Understanding the mechanisms by which accelerated immunological aging is induced and the ways in which a tumour such as MM influences this process is key to overcoming therapeutic barriers. A link between cellular mitochondrial dysfunction and the acquisition of an abnormal immune phenotype has recently been described and has widespread physiological consequence beyond the impact on the immune system. Here we outline our current understanding of normal immune aging, describe the mechanism of immunometabolic dysfunction in accelerating this process, and propose the role these processes are playing in the pathogenesis of MM.

Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.

There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

Neurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways.

Multiple sclerosis (MS) encompasses a chronic, irreversible, and predominantly immune-mediated disease of the central nervous system that leads to axonal degeneration, neuronal death, and several neurological symptoms. Although various immune therapies have reduced relapse rates and the severity of symptoms in relapsing-remitting MS, there is still no cure for this devastating disease. In this brief review, we discuss the role of mitochondria dysfunction in the progression of MS, focused on the possible role of Nrf2 signaling in orchestrating the impairment of critical cellular and molecular aspects such as reactive oxygen species (ROS) management, under neuroinflammation and neurodegeneration in MS. In this scenario, we propose a new potential downstream signaling of Nrf2 pathway, namely the opening of hemichannels and pannexons. These large-pore channels are known to modulate glial/neuronal function and ROS production as they are permeable to extracellular Ca2+ and release potentially harmful transmitters to the synaptic cleft. In this way, the Nrf2 dysfunction impairs not only the bioenergetics and metabolic properties of glial cells but also the proper antioxidant defense and energy supply that they provide to neurons.

Role of Mitochondrial Dysfunction in the Pathogenesis of Cisplatin-Induced Myotube Atrophy.

Muscle atrophy is commonly observed during cisplatin chemotherapy, leading to a reduced QOL in cancer patients. Reduced skeletal muscle mass caused by cisplatin treatment results from the activation of ubiquitin ligases-Atrogin-1 and MuRF1, but the precise mechanisms are poorly understood. In this study, we investigated the possible involvement of mitochondrial dysfunction, including reactive oxygen species (ROS) generation and ATP production, in cisplatin-induced muscle atrophy. Skeletal C2C12 myotubes were treated with cisplatin, and gene and protein expression were evaluated. Mitochondrial mass, membrane potential, and ROS levels were measured using fluorescent dyes. Mitochondrial respiratory function, ATP production rates, and glycolytic capacity were also analyzed using an extracellular flux analyzer. Metabolomic analyses were performed using gas chromatography-tandem mass spectrometry. Cisplatin treatment reduced myosin heavy chain expression by activating the ubiquitin-proteasome system. Increased ROS production was observed after cisplatin treatment, followed by significant changes in apoptosis-related gene expression and decrease in mitochondrial mass, membrane potential, respiration, and ATP production. Glycolytic capacity and tricarboxylic acid (TCA) cycle metabolite levels were reduced with cisplatin treatment. Mitochondria-targeted antioxidant mitoquinone mesylate prevented up-regulation of Atrogin-1 gene expression and restored myosin heavy chain levels, accompanied by a decrease in ROS generation, but not mitochondrial ATP production. We concluded that cisplatin-induced myotube atrophy was associated with mitochondrial dysfunction. Reducing ROS generation, rather than promoting ATP production, could be a useful therapeutic strategy for preventing cisplatin-induced muscle atrophy.

What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?

What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?

Novel Models of Crohn's Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells.

Crohn’s disease remains one of the challenging problems of modern medicine, and the development of new and effective and safer treatments against it is a dynamic field of research. To make such developments possible, it is important to understand the pathologic processes underlying the onset and progression of Crohn’s disease at the molecular and cellular levels. During the recent years, the involvement of mitochondrial dysfunction and associated chronic inflammation in these processes became evident. In this review, we discuss the published works on pathogenetic models of Crohn’s disease. These models make studying the role of mitochondrial dysfunction in the disease pathogenesis possible and advances the development of novel therapies.

Targeting p21‐highly‐expressing Senescent Cells Enhances Skeletal Muscle Function through Mitochondrial Function and Reactive Oxygen Species

BACKGROUNDThe accumulation of senescent cells is a hallmark of aging in the skeletal muscle which causes reactive oxygen species (ROS) and mitochondrial dysfunction. p21 is one of the major regulators and most recognized cellular markers for senescent cells. Recent evidence demonstrated that clearance of p21high cells enhances muscle function including grip strength, hanging endurance, and maximal walking speed in mice. However, it is still unclear how the muscle performance enhances through the clearance of p21high cells. One of the potential mechanisms is mitochondrial function and/or mitochondria‐derived ROS. Therefore, this study investigated the linkage between mitochondria and p21high cells in aging or high fat diet‐induced muscle dysfunction.METHODSFive p21‐Cre/+; +/+ (P) and p21‐Cre/+; DTA/+ (PD) obese mice fed by high fat diet were administrated with tamoxifen for twice. Five P lean mice fed by normal chow were adopted as normal control. We previously demonstrated that p21high cells accumulate in obese P mice, and can be eliminated in obese PD mice by tamoxifen treatment. Mitochondrial respiration was measured, by high‐resolution respirometry, in permeabilized muscle fibers from the soleus muscle. Mitochondria‐derive ROS production was determined using Amplex Red assays. One‐way ANOVAs with Bonferroni post‐hoc were used to determine differences between groups (P < 0.05).RESULTSReductions in complex I + II state 3 respiration were observed in p21‐Cre mice with high fat diet but the clearance of p21high cells using tamoxifen enhanced complex I + II state 3 respiration (Lean P: 35.2 ± 3.13 pmol·s‐1·mg‐1; Obese P: 17.45 ± 2.85 pmol·s‐1·mg‐1; Obese PD: 30.04 ± 3.19 pmol·s‐1·mg‐1; P < 0.05). State 4 respiration did not differ between groups (P > 0.05). Respiratory Control Ratio (RCR), defined as respiration in state 3 divided by respiration in state 4, significantly decreased in high fat diet group but clearing p21high cells restored respiratory function (Lean P: 4.20 ± 1.18; Obese P: 2.21 ± 1.11; Obese PD: 3.85 ± 1.60; P<0.05). Also, high fat diet increased mitochondrial ROS production, but tamoxifen treatment attenuated ROS production (Lean P: 10.16 ± 0.41 pmol·s‐1·mg‐1; Obese P: 26.83 ± 0.54 pmol·s‐1·mg‐1; Obese PD: 12.23 ± 0.54 pmol·s‐1·mg‐1; P<0.05).CONCLUSIONThese results demonstrated that p21high cells may play a causal role in mitochondrial dysfunction and ROS emission in the skeletal muscle with obesity and other chronic diseases. Therefore, targeting p21high cells may enhance muscle performance through decreasing mitochondria‐derived ROS and enhancing mitochondrial function.