Pub Date : 2025-11-01Epub 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":"2025-11-01","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}
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":"2025-11-01","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}
Pub Date : 2025-11-01Epub Date: 2025-07-19DOI: 10.1016/j.mito.2025.102069
Aniket Sawant , Irina Griķe , Baiba Vilne
Coronary Artery Diseases (CAD) contribute significantly to the global morbidity and mortality. While genome-wide association studies have identified numerous nuclear genomic variants linked to CAD, these account for less than 20 % of the disease’s estimated heritability (variation in disease risk attributed to genetic factors), suggesting the potential contribution of non-nuclear genetic elements, such as mitochondrial single-nucleotide variants (MT-SNVs). MT-SNVs may also influence lifestyle-related traits, which often interact with genetic predisposition to modulate CAD risk.
Hypothesis: MT-SNVs contribute to the unexplained heritability of CAD and may also be associated with lifestyle behaviours.
Methods
We analysed 203 high-quality common and low-frequency MT-SNVs (minor allele frequency > 0.01) in 20,400 CAD cases (myocardial infarction and/or revascularisation) from the UK Biobank after rigorous quality control and imputation. Associations between MT-SNVs and 85 quantitative food intake traits (FIQTs) and 23 established CAD risk factors (e.g., smoking status, lipid levels, physical activity) using both Frequentist and Bayesian methods. Correlation analyses were performed across these 108 lifestyle behaviours.
Results
Several MT-SNVs were nominally associated with the CAD status and lifestyle habits, including m.10873T > C (MT-ND4 gene), m.15301G > A (MT-CYB gene), m.8701A > G (MT-ATP6 gene), and m.9540T > C (MT-CO3). After adjusting for covariates, these associations did not remain statistically significant. CAD status was significantly but weakly correlated (|r| < 0.2) with 64 dietary preferences of the 108 lifestyle traits (Bonferroni-adjusted P < 0.05), indicating modest but widespread dietary pattern differences.
Conclusions
Our findings suggest that MT-SNVs may explain some of the CAD heritability. However, larger cohorts with more comprehensive mitochondrial data are needed to clarify their potential role.
冠状动脉疾病（CAD）是全球发病率和死亡率的重要组成部分。虽然全基因组关联研究已经确定了许多与CAD相关的核基因组变异，但这些变异占该疾病估计遗传力（遗传因素导致的疾病风险变异）的比例不到20% %，这表明非核遗传因素（如线粒体单核苷酸变异（mt - snv））可能起作用。mt - snv也可能影响与生活方式相关的特征，这些特征通常与调节CAD风险的遗传易感性相互作用。假设：mt - snv有助于CAD的无法解释的遗传性，也可能与生活方式行为有关。方法：我们分析了20,400例CAD（心肌梗死和/或血运重建）病例中203个高质量的常见和低频mt - snv（次要等位基因频率 > 0.01），经过严格的质量控制和imputation。mt - snv与85个定量食物摄入特征（FIQTs）和23个已确定的CAD危险因素（如吸烟状况、脂质水平、身体活动）之间的关联使用Frequentist和Bayesian方法。对这108种生活方式行为进行了相关性分析。结果：几种mt - snv名义上与CAD状态和生活习惯相关，包括m.10873T > C （MT-ND4基因）、m.15301G > A （MT-CYB基因）、m.8701A > G （MT-ATP6基因）和m.9540T > C （MT-CO3）。在调整协变量后，这些关联在统计上并不显著。结论：我们的研究结果表明，mt - snv可能解释了CAD的一些遗传性。然而，需要更大的队列和更全面的线粒体数据来阐明它们的潜在作用。
{"title":"Comprehensive analysis of the mitochondrial DNA variants using multivariate covariate and multiple-testing models to enhance reliability reveals potential associations with coronary artery disease traits and dietary preferences","authors":"Aniket Sawant , Irina Griķe , Baiba Vilne","doi":"10.1016/j.mito.2025.102069","DOIUrl":"10.1016/j.mito.2025.102069","url":null,"abstract":"<div><div>Coronary Artery Diseases (CAD) contribute significantly to the global morbidity and mortality. While genome-wide association studies have identified numerous nuclear genomic variants linked to CAD, these account for less than 20 % of the disease’s estimated heritability (variation in disease risk attributed to genetic factors), suggesting the potential contribution of non-nuclear genetic elements, such as mitochondrial single-nucleotide variants (MT-SNVs). MT-SNVs may also influence lifestyle-related traits, which often interact with genetic predisposition to modulate CAD risk.</div><div>Hypothesis: MT-SNVs contribute to the unexplained heritability of CAD and may also be associated with lifestyle behaviours.</div></div><div><h3>Methods</h3><div>We analysed 203 high-quality common and low-frequency MT-SNVs (minor allele frequency > 0.01) in 20,400 CAD cases (myocardial infarction and/or revascularisation) from the UK Biobank after rigorous quality control and imputation. Associations between MT-SNVs and 85 quantitative food intake traits (FIQTs) and 23 established CAD risk factors (e.g., smoking status, lipid levels, physical activity) using both Frequentist and Bayesian methods. Correlation analyses were performed across these 108 lifestyle behaviours.</div></div><div><h3>Results</h3><div>Several MT-SNVs were nominally associated with the CAD status and lifestyle habits, including m.10873T > C (MT-ND4 gene), m.15301G > A (MT-CYB gene), m.8701A > G (MT-ATP6 gene), and m.9540T > C (MT-CO3). After adjusting for covariates, these associations did not remain statistically significant. CAD status was significantly but weakly correlated (|r| < 0.2) with 64 dietary preferences of the 108 lifestyle traits (Bonferroni-adjusted P < 0.05), indicating modest but widespread dietary pattern differences.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that MT-SNVs may explain some of the CAD heritability. However, larger cohorts with more comprehensive mitochondrial data are needed to clarify their potential role.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"85 ","pages":"Article 102069"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682791","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 : 2025-11-01Epub 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":"2025-11-01","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 : 2025-09-01Epub Date: 2025-04-17DOI: 10.1016/j.mito.2025.102040
Isabel Amador-Martínez , Ana Karina Aranda-Rivera , Mauricio Raziel Martínez-Castañeda , José Pedraza-Chaverri
Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.
{"title":"Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases","authors":"Isabel Amador-Martínez , Ana Karina Aranda-Rivera , Mauricio Raziel Martínez-Castañeda , José Pedraza-Chaverri","doi":"10.1016/j.mito.2025.102040","DOIUrl":"10.1016/j.mito.2025.102040","url":null,"abstract":"<div><div>Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102040"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850285","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 : 2025-09-01Epub Date: 2025-06-18DOI: 10.1016/j.mito.2025.102061
Chieh-Wen Kuo , Hui-An Chen , Rai-Hseng Hsu , Chao-Szu Wu , Ching Hsu , Ming-Jen Lee , Yin-Hsiu Chien , Hsueh-Wen Hsueh , Feng-Jung Yang , Pi-Chuan Fan , Wen-Chin Weng , Ru-Jen Lin , Ta-Ching Chen , Chih-Chao Yang , Wang-Tso Lee , Wuh-Liang Hwu , Ni-Chung Lee
Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.
{"title":"Machine learning to predict mitochondrial diseases by phenotypes","authors":"Chieh-Wen Kuo , Hui-An Chen , Rai-Hseng Hsu , Chao-Szu Wu , Ching Hsu , Ming-Jen Lee , Yin-Hsiu Chien , Hsueh-Wen Hsueh , Feng-Jung Yang , Pi-Chuan Fan , Wen-Chin Weng , Ru-Jen Lin , Ta-Ching Chen , Chih-Chao Yang , Wang-Tso Lee , Wuh-Liang Hwu , Ni-Chung Lee","doi":"10.1016/j.mito.2025.102061","DOIUrl":"10.1016/j.mito.2025.102061","url":null,"abstract":"<div><div>Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102061"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329618","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 : 2025-09-01Epub Date: 2025-05-07DOI: 10.1016/j.mito.2025.102044
Angèle Nalbandian , Katrina J. Llewellyn , Arianna Gomez , Naomi Walker , Hailing Su , Andrew Dunnigan , Marilyn Chwa , Jouni Vesa , M.C. Kenney , Virginia E. Kimonis
{"title":"Corrigendum to “In vitro studies in VCP-associated multisystem proteinopathy suggest altered mitochondrial bioenergetics” [Mitochondrion 22 (2015) 1–8]","authors":"Angèle Nalbandian , Katrina J. Llewellyn , Arianna Gomez , Naomi Walker , Hailing Su , Andrew Dunnigan , Marilyn Chwa , Jouni Vesa , M.C. Kenney , Virginia E. Kimonis","doi":"10.1016/j.mito.2025.102044","DOIUrl":"10.1016/j.mito.2025.102044","url":null,"abstract":"","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102044"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032731","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 : 2025-09-01Epub Date: 2025-04-18DOI: 10.1016/j.mito.2025.102042
Elly H. Shin , Quinn Le , Rachel Barboza , Amanda Morin , Shiva M. Singh , Christina A. Castellani
Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.
{"title":"Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling","authors":"Elly H. Shin , Quinn Le , Rachel Barboza , Amanda Morin , Shiva M. Singh , Christina A. Castellani","doi":"10.1016/j.mito.2025.102042","DOIUrl":"10.1016/j.mito.2025.102042","url":null,"abstract":"<div><div>Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102042"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874549","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 : 2025-09-01Epub Date: 2025-03-29DOI: 10.1016/j.mito.2025.102033
Catherine Kelly , Marissa Cross , Alex Junker , Kris Englestad , Xiomara Q. Rosales , Michio Hirano , Caroline Trumpff , Martin Picard
Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy transformation capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients’ perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the Stress, Health and Emotion Survey (SHES) to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either ‘good’ (happy, calm) or ‘bad’ (stress, sad) emotional days. On average, patients reported that most symptoms were better on “good” emotional days (p < 0.0001) and worse on “bad” emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models to understand the psychobiological factors that influence the course of mitochondrial diseases.
{"title":"Perceived association of mood and symptom severity in adults with mitochondrial diseases","authors":"Catherine Kelly , Marissa Cross , Alex Junker , Kris Englestad , Xiomara Q. Rosales , Michio Hirano , Caroline Trumpff , Martin Picard","doi":"10.1016/j.mito.2025.102033","DOIUrl":"10.1016/j.mito.2025.102033","url":null,"abstract":"<div><div>Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy transformation capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients’ perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the <em>Stress, Health and Emotion Survey (SHES)</em> to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either ‘good’ (happy, calm) or ‘bad’ (stress, sad) emotional days. On average, patients reported that most symptoms were better on “good” emotional days (p < 0.0001) and worse on “bad” emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models to understand the psychobiological factors that influence the course of mitochondrial diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102033"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753436","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 : 2025-09-01Epub Date: 2025-04-18DOI: 10.1016/j.mito.2025.102043
Valerie Sackmann , Nasna Nassir , Satoshi Tanikawa , Shelley L. Forrest , Helen Chasiotis , Jun Li , Shehzad Hanif , Ivan Martinez-Valbuena , Maria Carmela Tartaglia , Anthony E. Lang , Mohammed Uddin , Alexei Verkhratsky , Gabor G. Kovacs
Progressive supranuclear palsy (PSP) is a main form of idiopathic tauopathy characterized neuropathologically by subcortical neurofibrillary tangles in neurons, oligodendroglial coiled bodies, and tufted astrocytes, which follow sequential distribution in the human brain. Mitochondrial dysfunction is thought to be a contributor to many neurodegenerative diseases, but its role in PSP at the cellular level remains incompletely understood. To address this, we performed cell-specific morphometric analysis of mitochondrial markers in post-mortem tissues from motor cortex of PSP patients and non-diseased controls (n = 5 each) followed by single-nuclear transcriptomics (n = 3 each) to identify changes in genes that regulate mitochondrial function. We treated iCell astrocytes with PSP brain homogenates and isolated viable astrocytes from multiple regions of PSP-affected brains. We found that PSP is characterized by significant mitochondrial changes in neurons and astrocytes at the immunohistochemical level, particularly in complex I, with distinct transcriptomic responses across cell types. Glial cells exhibited upregulation of pathways associated with mitochondrial function. In contrast, excitatory and inhibitory neurons showed downregulation in these pathways, indicating impaired mitochondrial function. Astrocytes derived from different human brain regions express varied levels of GFAP and EAAT1 immunoreactivity. Astrocytic tau pathology in cell culture derived from postmortem PSP brains mirrors that seen in corresponding brain tissue histology. Tau pathology in human astrocyte cell culture is associated with clumps of mitochondria potentially associated with impairment in their neuron supportive function. Our results underscore selective complex I damage and cell-type specific patterns that differentiate PSP from other neurodegenerative diseases.
{"title":"Cell-specific mitochondrial response in progressive supranuclear palsy","authors":"Valerie Sackmann , Nasna Nassir , Satoshi Tanikawa , Shelley L. Forrest , Helen Chasiotis , Jun Li , Shehzad Hanif , Ivan Martinez-Valbuena , Maria Carmela Tartaglia , Anthony E. Lang , Mohammed Uddin , Alexei Verkhratsky , Gabor G. Kovacs","doi":"10.1016/j.mito.2025.102043","DOIUrl":"10.1016/j.mito.2025.102043","url":null,"abstract":"<div><div>Progressive supranuclear palsy (PSP) is a main form of idiopathic tauopathy characterized neuropathologically by subcortical neurofibrillary tangles in neurons, oligodendroglial coiled bodies, and tufted astrocytes, which follow sequential distribution in the human brain. Mitochondrial dysfunction is thought to be a contributor to many neurodegenerative diseases, but its role in PSP at the cellular level remains incompletely understood. To address this, we performed cell-specific morphometric analysis of mitochondrial markers in post-mortem tissues from motor cortex of PSP patients and non-diseased controls (n = 5 each) followed by single-nuclear transcriptomics (n = 3 each) to identify changes in genes that regulate mitochondrial function. We treated iCell astrocytes with PSP brain homogenates and isolated viable astrocytes from multiple regions of PSP-affected brains. We found that PSP is characterized by significant mitochondrial changes in neurons and astrocytes at the immunohistochemical level, particularly in complex I, with distinct transcriptomic responses across cell types. Glial cells exhibited upregulation of pathways associated with mitochondrial function. In contrast, excitatory and inhibitory neurons showed downregulation in these pathways, indicating impaired mitochondrial function. Astrocytes derived from different human brain regions express varied levels of GFAP and EAAT1 immunoreactivity. Astrocytic tau pathology in cell culture derived from postmortem PSP brains mirrors that seen in corresponding brain tissue histology. Tau pathology in human astrocyte cell culture is associated with clumps of mitochondria potentially associated with impairment in their neuron supportive function. Our results underscore selective complex I damage and cell-type specific patterns that differentiate PSP from other neurodegenerative diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"84 ","pages":"Article 102043"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882467","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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