Mitochondrion最新文献

{"title":"Pearson syndrome with atypical presentation of short stature and atypical limb proportions – First reported case in Slovakia","authors":"Gabriela Bľandová ,&nbsp;Michaela Murgašová ,&nbsp;Adam Markocsy ,&nbsp;Marian Baldovič ,&nbsp;Gabriela Krasňanská ,&nbsp;Vladimír Eliaš ,&nbsp;Vanda Repiská ,&nbsp;Michal Konečný","doi":"10.1016/j.mito.2025.102079","DOIUrl":"10.1016/j.mito.2025.102079","url":null,"abstract":"<div><div>In this case report, we describe an individual with Pearson syndrome, representing the first reported case in Slovakia. The patient was 1.5-year-old boy with pancytopenia including macrocytic anemia, neutropenia and thrombocytopenia, pancreatic insufficiency, hepatopathy, psychomotor development delay, short stature and failure to thrive. The patient also had atypical symptoms for Pearson syndrome, including atypical limb proportions and facial dysmorphism, which contributed to the delay in correct diagnosis. In the whole exome sequencing (WES) analysis, virtual panels targeting genes associated with inborn errors of immunity and anemia were selected based on the patient’s clinical phenotype, however no pathogenic variant was identified within these panels. During the evaluation of secondary findings, a pathogenic deletion, m.10952_15371del, was detected in mitochondrial DNA in a heteroplasmic state (55.8% in peripheral blood), leading to the diagnosis. Subsequently, MLPA analysis confirmed this deletion in other patient tissues (urine, bone marrow aspirate, buccal swab) with the highest level of heteroplasmy (70%) detected in the urine sample. Our study emphasizes the importance of a comprehensive diagnostic approach, including the analysis of several tissues, especially in the diagnosis of clinically complex mitochondrial diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102079"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted mitochondrial metabolism for anti-tumor therapy","authors":"Chi Yan ,&nbsp;Xuefang Li ,&nbsp;Pei Wei ,&nbsp;Xiaoyan Zhang ,&nbsp;Haining Wang ,&nbsp;Zhigang Chen ,&nbsp;Fei Lin ,&nbsp;Guangjian Lu","doi":"10.1016/j.mito.2025.102073","DOIUrl":"10.1016/j.mito.2025.102073","url":null,"abstract":"<div><div>Cancer has become a focal point of concern owing to its escalating incidence and mortality rates. However, traditional treatment modalities are encumbered by inherent constraints, posing ongoing challenges in achieving definitive cancer eradication. Mitochondria, crucial for cellular growth and physiological homeostasis, manifest distinctive structural and metabolic alterations within cancerous cells compared to their normal counterparts. Targeting aberrant mitochondrial metabolism in tumor cells has emerged as a promising therapeutic strategy, capitalizing on the precision, efficacy, and minimal adverse effects associated with targeted therapeutic approaches. However, due to the complexity of tumor cells, the specific mechanism underlying the role of mitochondria in tumor development and new anti-tumor drugs targeting mitochondrial metabolism still need to be further studied. This review focuses on studies that target mitochondrial DNA, oxidative phosphorylation, mitochondrial energy metabolism, and amino acid metabolism in tumor cells, elucidating the methods involved in targeting mitochondrial metabolism and underscoring the significance of future studies in developing therapies targeting mitochondrial metabolism for cancer treatment.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102073"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial quality control in exercise-mitigated muscular atrophy.","authors":"Jingcheng Fan, Xin Wen, Xuemei Duan, Xinyi Zhu, Jianzheng Bai, Tan Zhang","doi":"10.1016/j.mito.2025.102074","DOIUrl":"10.1016/j.mito.2025.102074","url":null,"abstract":"<p><p>Muscle atrophy is a loss of muscle mass, posing a huge burden on patients and society. Increased protein degradation, decreased protein synthesis, inflammatory response, oxidative stress, and mitochondrial dysfunction are risk factors of muscular atrophy. Mitochondrial quality control (MQC) processes maintain mitochondrial health, which is essential to maintain skeletal muscle structural and functional integrity. Of note, it is widely acknowledged that regular exercise induces significant improvements in muscular atrophy. Mechanistically, exercise reinforces mitochondrial function through MQC, as well as mitigate muscular atrophy. However, the role and molecular mechanism of MQC in exercise-attenuated muscular atrophy have not yet fully elucidated. Here, we review the current knowledge relevant to MQC in the context of muscular atrophy, and focus on MQC in exercise-mediated anti-atrophic effect, which may be conductive to muscular atrophy prevention and therapy through targeting mitochondria.</p>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":" ","pages":"102074"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mutations in MTERF3: First report of a new genetic cause in two Chinese patients with developmental delay, intermittent hypoglycemia and metabolic acidosis","authors":"Ruoyu Duan ,&nbsp;Refiloe Laurentinah Mahlatsi ,&nbsp;Ya Wang ,&nbsp;Chaolong Xu ,&nbsp;Mingzhao Wang ,&nbsp;Zhuo Zou ,&nbsp;Zhimei Liu ,&nbsp;Huafang Jiang ,&nbsp;Xin Duan ,&nbsp;Jie Deng ,&nbsp;Minhan Song ,&nbsp;Yun Liu ,&nbsp;Hezhi Fang ,&nbsp;JianXin Lyu ,&nbsp;Fang Fang","doi":"10.1016/j.mito.2025.102059","DOIUrl":"10.1016/j.mito.2025.102059","url":null,"abstract":"<div><div>MTERF3, a negative regulator of mtDNA transcription, was first identified in 2007.Recent studies have revealed the pivotal role of MTERF3 throughout the entire lifecycle of mtDNA. However, no disease phenotypes have been linked to this gene till now. Genetic testing was performed on two unrelated families. Mitochondrial respiration and OXPHOS complex activity were assessed in patient-derived fibroblasts. An <em>MTERF3</em> knockdown HEK293 cell line was generated, followed by rescue experiments with wild-type and mutant <em>MTERF3</em>. Two patients mainly presented with developmental delay. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C &gt; T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A &gt; Gp.(Met315Val) in Patient 2. Patient’s fibroblasts and <em>MTERF3</em> knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type <em>MTERF3</em> expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction. This study identifies a novel mitochondrial disease phenotype and establishes the first association with MTERF3, expanding the mitochondrial disease spectrum and offering insights into the clinical relevance of the MTERF family.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102059"},"PeriodicalIF":3.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Tunisian POLG mutation expands the clinical spectrum of POLG-related disorders","authors":"Abir Zioudi ,&nbsp;Ismail Gouiza ,&nbsp;Said Galai ,&nbsp;Meriem Hechmi ,&nbsp;Hedia Klaa ,&nbsp;Zouhour Miladi ,&nbsp;Thouraya Ben Younes ,&nbsp;Hanene Benrhouma ,&nbsp;Ilhem Ben Youssef-Turki ,&nbsp;Souheil Omar ,&nbsp;Guy Lenaers ,&nbsp;Rym Kefi ,&nbsp;Neziha Gouider-Khouja ,&nbsp;Ichraf Kraoua","doi":"10.1016/j.mito.2025.102071","DOIUrl":"10.1016/j.mito.2025.102071","url":null,"abstract":"<div><div>Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE) is a rare and fatal mitochondrial disorder caused by biallelic mutations in the <em>TYMP</em> gene. In rare cases, it can be caused by pathogenic variants in the <em>POLG</em> gene, with a clinical presentation similar to that of <em>TYMP</em>-related MNGIE, except for the absence of leukoencephalopathy.</div><div>Here we report the cases of six Tunisian patients presenting with a homogeneous clinical MNGIE-like phenotype, characterized by an early infantile onset. Key features included psychomotor delay or regression, peripheral neuropathy, gastrointestinal disturbances, hypotrophy or growth retardation, and elevated cerebrospinal fluid protein levels. All patients originated from the same governorate and carried the same homozygous <em>POLG</em> variant c.2391G &gt; T (p.Met797Ile), which may suggest a founder effect.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102071"},"PeriodicalIF":3.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKM2 is a key regulator of cardiac lipid metabolism in mice","authors":"Katie C.Y. Lee ,&nbsp;Allison L. Williams ,&nbsp;Anastasia Fujimoto ,&nbsp;Mariana Gerschenson ,&nbsp;Connor Schuller ,&nbsp;Noemi Polgar ,&nbsp;Naghum Alfulaij ,&nbsp;Briana K. Shimada ,&nbsp;Lucia A. Seale ,&nbsp;Ralph V. Shohet","doi":"10.1016/j.mito.2025.102070","DOIUrl":"10.1016/j.mito.2025.102070","url":null,"abstract":"<div><div>Deficiencies in lipid metabolism can have severe consequences for cardiac function. We previously showed that regulating glucose flux by pyruvate kinase 2 (PKM2) affects lipid synthesis and droplet abundance in cardiomyocytes. This study aims to examine how PKM2 regulates lipid metabolism in the heart.</div><div>Indirect calorimetry suggested similar whole-body metabolism of PKM2 knockout (PKM2^-/-) and control (PKM2^fl/fl) young mice (2–3 months), but indicated that lipids were utilized to a greater degree in aged (1-year) PKM2^-/- mice compared to controls. Metabolic chamber studies also revealed an overall negative energy balance that contributed to reduced exercise tolerance in aged PKM2^-/- mice. Metabolomics showed substantially lower carnitine levels in PKM2^-/- cardiomyocyte fractions (CM), alongside increased circulating and cardiac dicarboxylic acids, as well as reduced mitochondrial palmitate oxidation in PKM2^-/- CM. We also noted a sex-specific difference in which female PKM2^-/- mice exhibited greater high-fat diet (HFD)-induced hyperglycemia and weight gain compared to PKM2^fl/fl females, while male PKM2^-/- mice fed a HFD were comparatively leaner than their PKM2^fl/fl counterparts.</div><div>PKM2^-/- mice have aberrations in lipid metabolism that worsen with age, shifting whole-body metabolism towards a preference for lipid utilization. This may lead to a decline in aerobic capacity during exercise in aged PKM2^-/- mice. PKM2^-/- CM also display compromised mitochondrial lipid metabolism due to carnitine deficiency. Challenging PKM2^-/- mice with a HFD revealed sex-dependent differences in glycemic control and body weight. Our results indicate a role for PKM2 in sustaining the homeostasis of cardiac and whole-body lipid metabolism that contributes to overall physiological fitness.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102070"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease","authors":"Luisa Zupin ,&nbsp;Valeria Capaci ,&nbsp;Maria Teresa Bonati ,&nbsp;Eleonora Lamantea ,&nbsp;Muhammad Suleman ,&nbsp;Andrea Marsala ,&nbsp;Fulvio Celsi ,&nbsp;Beatrice Spedicati ,&nbsp;Sergio Crovella ,&nbsp;Giulia Gortani ,&nbsp;Giorgia Girotto ,&nbsp;Irene Bruno ,&nbsp;Massimo Zeviani","doi":"10.1016/j.mito.2025.102080","DOIUrl":"10.1016/j.mito.2025.102080","url":null,"abstract":"<div><div>The diagnosis of disorders associated with mitochondrial DNA (mtDNA) variants presents substantial complexity due to their genetic and clinical heterogeneity, which is largely influenced by mtDNA heteroplasmy. However, the level of heteroplasmy alone is often not sufficient to predict the clinical phenotype including its severity and progression.</div><div>This study concerns the characterization of the m.8357T &gt; C variant in the <em>MT-TK</em> gene, encoding for mt-tRNA-Lys found in two pediatric siblings. Both had symptoms suggestive of a mitochondrial disease, including severe hearing loss, easy fatigability, decreased activity of mitochondrial complex I in muscle samples, epilepsy, metabolic acidosis with hyperkalemia, and mild kidney impairment.</div><div>The m.8357T &gt; C mtDNA variant was homoplasmic in muscle, blood, urine and fibroblasts. Immortalized fibroblasts from the patients showed reduced activity of mitochondrial complexes I, III and IV, decreased mitochondrial respiration, and abnormal depolarization of the mitochondrial membrane potential. The mt-tRNA-Lys levels were reduced as compared to the mt-tRNA-Leu (UUR) or the snRNA encoded by <em>RNU6B</em> nuclear gene; the level of three mitochondrial DNA encoded proteins was decreased, altogether suggesting a defective translation machinery in cells carrying the variant. Consistently, fibroblasts from the mother, who had only mild hearing loss, despite high level of heteroplasmy, showed some biochemical abnormalities, however milder than in her daughter and son. Contrariwise, their maternal aunt, who showed intellectual disability, mild hearing loss, easy fatigability and weakness was also virtually homoplasmic for the m.8357T &gt; C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T &gt; C variant but only in condition of homoplasmy.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102080"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA variants in normal skins: Insights into prevalent pathogenic variants and quality control surveillance","authors":"Kohta Nakamura ,&nbsp;Yasunari Sato ,&nbsp;Masao Hashimoto ,&nbsp;Naoyuki Matsumoto ,&nbsp;Sachiko Nitta ,&nbsp;Yasushi Okazaki ,&nbsp;Yasuo Miyoshi ,&nbsp;Hiroki Nagase","doi":"10.1016/j.mito.2025.102081","DOIUrl":"10.1016/j.mito.2025.102081","url":null,"abstract":"<div><div>Mitochondrial genome diversity in normal tissues remains poorly understood due to 100 to 1000 copies of mitochondrial DNA in a cell. This study analyzed mitochondrial DNA variants in two distant sites of normal skin tissues from 119 breast surgery cases using deep sequencing. We identified 1337 variants across the mitochondrial genome (59.1 % in coding region). Intriguingly variants were categorized two groups, homoplasmic (81.1 %) or low heteroplasmy rate group (14.1 %). Even MITOMAP pathogenic variants, two out of eight were homoplasmic, common in several patients, and found in both skin sites of the same individual, while six heteroplasmic pathogenic variants were identified in a single patient with &lt; 5 % heteroplasmy rates, half only detected in a single skin site with &lt; 2 % rates. Pathogenic mutations predicted by AlphaMissense were significantly less common in the homoplasmic group (30/1085) but more common in the heteroplasmic group (216/431). Significant increases of mitochondrial copy number were also repeatedly detected in cases with pathogenic variants. This study provides new insights into the diversity of mitochondrial genome and the complexity of mitochondrial homeostasis in normal skin tissue, including the possibility of evading pathogenic mutations through quality control surveillance and the restoration of mitochondrial function due to increase in copy number.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102081"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational discovery of novel SIRT4 inhibitors for cardiac hypertrophy treatment","authors":"Vaishnavi Jena,&nbsp;B Aparna Naidu,&nbsp;Deepak Sharma,&nbsp;Praisy Joy Bell I,&nbsp;Rajiniraja Muniyan","doi":"10.1016/j.mito.2025.102076","DOIUrl":"10.1016/j.mito.2025.102076","url":null,"abstract":"<div><div>Cardiac hypertrophy is characterized by the enlargement of the heart muscle, often resulting from conditions such as hypertrophic cardiomyopathy (HCM) and physiological hypertrophy. SIRT4 plays a crucial role in cardiac hypertrophy, primarily through its regulation of oxidative stress and mitochondrial function. Therefore, downregulating SIRT4 could help slow the progression of cardiac hypertrophy. This study investigates novel therapeutic approaches for cardiac hypertrophy through various computational strategies, such as Virtual screening, ADMET predictions, molecular docking, and molecular dynamics simulations, to identify potential drug candidates, DB12561 (Hit2), that could inhibit the SIRT4 protein.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102076"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitotherapy Restores mitochondrial function and improves cognitive deficits in Alzheimer’s disease","authors":"Tulika Gupta ,&nbsp;Asha Rao ,&nbsp;Veena Devi ,&nbsp;Lalita Kumari ,&nbsp;Akshita Negi ,&nbsp;Munish Kumar ,&nbsp;Ranjana Bharti ,&nbsp;Bikash Medhi","doi":"10.1016/j.mito.2025.102077","DOIUrl":"10.1016/j.mito.2025.102077","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a hallmark of Alzheimer’s disease (AD), contributing to cognitive decline. This study explores the therapeutic potential of mitochondrial transplantation in mitigating cognitive decline in AD. Structurally and functionally characterized mitochondria from young rat brains were intravenously transplanted into AD rats. Confocal imaging confirmed integration of exogenous tagged mitochondria into hippocampal tissue. Post-mitotherapy, we noted significant cognitive improvement by neurobehavioral tests and significant reduction in protein levels of amyloid precursor protein. Further mitochondrial functional parameters improved; reduced oxidative stress, improved mitochondrial membrane potential, and calcium homeostasis. These findings highlight mitotherapy as a promising strategy for treating Alzheimer’s disease.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102077"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}