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 < 5 % heteroplasmy rates, half only detected in a single skin site with < 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.
{"title":"Mitochondrial DNA variants in normal skins: Insights into prevalent pathogenic variants and quality control surveillance","authors":"Kohta Nakamura , Yasunari Sato , Masao Hashimoto , Naoyuki Matsumoto , Sachiko Nitta , Yasushi Okazaki , Yasuo Miyoshi , 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 < 5 % heteroplasmy rates, half only detected in a single skin site with < 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":"2025-09-09","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}
Pub Date : 2025-08-18DOI: 10.1016/j.mito.2025.102079
Gabriela Bľandová , Michaela Murgašová , Adam Markocsy , Marian Baldovič , Gabriela Krasňanská , Vladimír Eliaš , Vanda Repiská , Michal Konečný
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.
{"title":"Pearson syndrome with atypical presentation of short stature and atypical limb proportions – First reported case in Slovakia","authors":"Gabriela Bľandová , Michaela Murgašová , Adam Markocsy , Marian Baldovič , Gabriela Krasňanská , Vladimír Eliaš , Vanda Repiská , 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":"2025-08-18","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}
Pub Date : 2025-08-18DOI: 10.1016/j.mito.2025.102080
Luisa Zupin , Valeria Capaci , Maria Teresa Bonati , Eleonora Lamantea , Muhammad Suleman , Andrea Marsala , Fulvio Celsi , Beatrice Spedicati , Sergio Crovella , Giulia Gortani , Giorgia Girotto , Irene Bruno , Massimo Zeviani
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.
This study concerns the characterization of the m.8357T > C variant in the MT-TK 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.
The m.8357T > 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 RNU6B 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 > C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T > C variant but only in condition of homoplasmy.
{"title":"The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease","authors":"Luisa Zupin , Valeria Capaci , Maria Teresa Bonati , Eleonora Lamantea , Muhammad Suleman , Andrea Marsala , Fulvio Celsi , Beatrice Spedicati , Sergio Crovella , Giulia Gortani , Giorgia Girotto , Irene Bruno , 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 > 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 > 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 > C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T > C variant but only in condition of homoplasmy.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102080"},"PeriodicalIF":4.5,"publicationDate":"2025-08-18","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}
Pub Date : 2025-08-18DOI: 10.1016/j.mito.2025.102076
Vaishnavi Jena, B Aparna Naidu, Deepak Sharma, Praisy Joy Bell I, Rajiniraja Muniyan
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.
{"title":"Computational discovery of novel SIRT4 inhibitors for cardiac hypertrophy treatment","authors":"Vaishnavi Jena, B Aparna Naidu, Deepak Sharma, Praisy Joy Bell I, 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":"2025-08-18","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}
India bears the largest burden of tuberculosis (TB) cases in the world. Prior studies have highlighted significantly higher pulmonary TB among the Sahariya tribal population in Central India. The disease susceptibility of a population to disease may be influenced by genetic ancestry. In this context, we investigated the maternal genetic ancestry of the Sahariya in relation to their neighbouring tribal populations. For this study, we used the largest available dataset (n = 729), comprising 140 Sahariya individuals and 589 individuals from adjacent caste and tribal groups (including 50 newly sequenced samples). Our detailed mtDNA analysis revealed the exclusive presence of two rare haplogroups N5 and X2 which are completely absent in neighbouring tribal and caste populations. Further examination of the phylogeographic origins of the branches of haplogroups N5 and X2 suggests that these unique founder haplogroup branches (N5a and X2a) were likely introduced into the Sahariya from the western regions of the Indian subcontinent. The temporal expansion of these haplogroups indicates a gene flow from the western area to the Sahariya population during the early Iron Age. In addition to that, we have also analysed 33 SNPs for six TB-associated genes. We observed a single SNP (rs4958847-IRGM1) where the minor allele frequency was significantly different in Sahariya with their neighbouring populations. Consequently, our analysis of maternal genetic ancestry and known associated autosomal genes provides insights that may help explain the higher prevalence of TB among the Sahariya compared to their neighbouring populations.
{"title":"Outlier maternal haplogroups N5 and X2 and their potential role in elevated tuberculosis prevalence among the Sahariya tribe","authors":"Debashruti Das , Prajjval Pratap Singh , Shailesh Desai , Rahul Kumar Mishra , Pankaj Shrivastava , Prashanth Suravajhala , Rakesh Tamang , Gyaneshwer Chaubey","doi":"10.1016/j.mito.2025.102078","DOIUrl":"10.1016/j.mito.2025.102078","url":null,"abstract":"<div><div>India bears the largest burden of tuberculosis (TB) cases in the world. Prior studies have highlighted significantly higher pulmonary TB among the Sahariya tribal population in Central India. The disease susceptibility of a population to disease may be influenced by genetic ancestry. In this context, we investigated the maternal genetic ancestry of the Sahariya in relation to their neighbouring tribal populations. For this study, we used the largest available dataset (n = 729), comprising 140 Sahariya individuals and 589 individuals from adjacent caste and tribal groups (including 50 newly sequenced samples). Our detailed mtDNA analysis revealed the exclusive presence of two rare haplogroups N5 and X2 which are completely absent in neighbouring tribal and caste populations. Further examination of the phylogeographic origins of the branches of haplogroups N5 and X2 suggests that these unique founder haplogroup branches (N5a and X2a) were likely introduced into the Sahariya from the western regions of the Indian subcontinent. The temporal expansion of these haplogroups indicates a gene flow from the western area to the Sahariya population during the early Iron Age. In addition to that, we have also analysed 33 SNPs for six TB-associated genes. We observed a single SNP (rs4958847-<em>IRGM1</em>) where the minor allele frequency was significantly different in Sahariya with their neighbouring populations. Consequently, our analysis of maternal genetic ancestry and known associated autosomal genes provides insights that may help explain the higher prevalence of TB among the Sahariya compared to their neighbouring populations.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102078"},"PeriodicalIF":4.5,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883186","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}
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.
{"title":"Mitotherapy Restores mitochondrial function and improves cognitive deficits in Alzheimer’s disease","authors":"Tulika Gupta , Asha Rao , Veena Devi , Lalita Kumari , Akshita Negi , Munish Kumar , Ranjana Bharti , 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":"2025-08-15","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}
Pub Date : 2025-07-28DOI: 10.1016/j.mito.2025.102075
Sabrina Champsi, David A. Hood
Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.
{"title":"Role of Prohibitins as Guardians of mitochondrial homeostasis","authors":"Sabrina Champsi, David A. Hood","doi":"10.1016/j.mito.2025.102075","DOIUrl":"10.1016/j.mito.2025.102075","url":null,"abstract":"<div><div>Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102075"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753790","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}
Pub Date : 2025-07-28DOI: 10.1016/j.mito.2025.102072
David P. Maison , Vedbar S. Khadka , Isam Mohd-Ibrahim , Michael J. Peluso , Timothy J. Henrich , Youping Deng , Mariana Gerschenson
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has led to millions of cases of Long COVID worldwide. Long COVID is a phenomenon characterized by persistent and debilitating mental and physical symptoms following acute infection. Despite ongoing research, trials, and considerable progress in understanding Long COVID, its exact causes remain only partially understood, with current hypotheses addressing specific aspects of the condition. We conducted one of the most comprehensive meta-analyses to date of all quality bulk RNA-seq studies worldwide from the COVID-19 pandemic and show significant mitochondrial transcript changes in the peripheral immune system of people with Long COVID, with unexpectedly low levels of intracellular viral RNA in Long COVID. This extensive analysis, which includes 26 studies and 1,272 individuals, shows that mononuclear cells, PBMC, and granulocytes from Long COVID patients exhibit significant alterations in mitochondrial genes and related processes. These findings likely represent the true transcriptomic landscape of Long COVID across diverse datasets, highlighting the long-lasting impacts of SARS-CoV-2 on peripheral immune function. In combination with other ex vivo and proteomics studies showing mitochondrial dysfunction, our results suggest critical new directions, such as the potential role of clonal hematopoiesis and infected seed cells. This work highlights the need for further investigation into the mechanisms underlying these immune changes and persistent symptoms in people with Long COVID. These findings will serve as a foundation for defining the paradigm underlying the biological mechanisms of Long COVID, driving research into the peripheral immune system, bone marrow, and mitochondria.
{"title":"Peripheral immune progression to long COVID is associated with mitochondrial gene transcription: A meta-analysis","authors":"David P. Maison , Vedbar S. Khadka , Isam Mohd-Ibrahim , Michael J. Peluso , Timothy J. Henrich , Youping Deng , Mariana Gerschenson","doi":"10.1016/j.mito.2025.102072","DOIUrl":"10.1016/j.mito.2025.102072","url":null,"abstract":"<div><div>SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has led to millions of cases of Long COVID worldwide. Long COVID is a phenomenon characterized by persistent and debilitating mental and physical symptoms following acute infection. Despite ongoing research, trials, and considerable progress in understanding Long COVID, its exact causes remain only partially understood, with current hypotheses addressing specific aspects of the condition. We conducted one of the most comprehensive meta-analyses to date of all quality bulk RNA-seq studies worldwide from the COVID-19 pandemic and show significant mitochondrial transcript changes in the peripheral immune system of people with Long COVID, with unexpectedly low levels of intracellular viral RNA in Long COVID. This extensive analysis, which includes 26 studies and 1,272 individuals, shows that mononuclear cells, PBMC, and granulocytes from Long COVID patients exhibit significant alterations in mitochondrial genes and related processes. These findings likely represent the true transcriptomic landscape of Long COVID across diverse datasets, highlighting the long-lasting impacts of SARS-CoV-2 on peripheral immune function. In combination with other ex vivo and proteomics studies showing mitochondrial dysfunction, our results suggest critical new directions, such as the potential role of clonal hematopoiesis and infected seed cells. This work highlights the need for further investigation into the mechanisms underlying these immune changes and persistent symptoms in people with Long COVID. These findings will serve as a foundation for defining the paradigm underlying the biological mechanisms of Long COVID, driving research into the peripheral immune system, bone marrow, and mitochondria.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102072"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723345","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}
Pub Date : 2025-07-27DOI: 10.1016/j.mito.2025.102073
Chi Yan , Xuefang Li , Pei Wei , Xiaoyan Zhang , Haining Wang , Zhigang Chen , Fei Lin , Guangjian Lu
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.
{"title":"Targeted mitochondrial metabolism for anti-tumor therapy","authors":"Chi Yan , Xuefang Li , Pei Wei , Xiaoyan Zhang , Haining Wang , Zhigang Chen , Fei Lin , 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":"2025-07-27","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}
Pub Date : 2025-07-22DOI: 10.1016/j.mito.2025.102070
Katie C.Y. Lee , Allison L. Williams , Anastasia Fujimoto , Mariana Gerschenson , Connor Schuller , Noemi Polgar , Naghum Alfulaij , Briana K. Shimada , Lucia A. Seale , Ralph V. Shohet
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.
Indirect calorimetry suggested similar whole-body metabolism of PKM2 knockout (PKM2-/-) and control (PKM2fl/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 PKM2fl/fl females, while male PKM2-/- mice fed a HFD were comparatively leaner than their PKM2fl/fl counterparts.
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.
{"title":"PKM2 is a key regulator of cardiac lipid metabolism in mice","authors":"Katie C.Y. Lee , Allison L. Williams , Anastasia Fujimoto , Mariana Gerschenson , Connor Schuller , Noemi Polgar , Naghum Alfulaij , Briana K. Shimada , Lucia A. Seale , 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<sup>-/-</sup>) and control (PKM2<sup>fl/fl</sup>) young mice (2–3 months), but indicated that lipids were utilized to a greater degree in aged (1-year) PKM2<sup>-/-</sup> mice compared to controls. Metabolic chamber studies also revealed an overall negative energy balance that contributed to reduced exercise tolerance in aged PKM2<sup>-/-</sup> mice. Metabolomics showed substantially lower carnitine levels in PKM2<sup>-/-</sup> cardiomyocyte fractions (CM), alongside increased circulating and cardiac dicarboxylic acids, as well as reduced mitochondrial palmitate oxidation in PKM2<sup>-/-</sup> CM. We also noted a sex-specific difference in which female PKM2<sup>-/-</sup> mice exhibited greater high-fat diet (HFD)-induced hyperglycemia and weight gain compared to PKM2<sup>fl/fl</sup> females, while male PKM2<sup>-/-</sup> mice fed a HFD were comparatively leaner than their PKM2<sup>fl/fl</sup> counterparts.</div><div>PKM2<sup>-/-</sup> 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<sup>-/-</sup> mice. PKM2<sup>-/-</sup> CM also display compromised mitochondrial lipid metabolism due to carnitine deficiency. Challenging PKM2<sup>-/-</sup> 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":"2025-07-22","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}
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