Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by hyperproliferation and remodeling of the pulmonary vasculature, primarily affecting pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). Although several pharmacological agents target the known signaling pathways in these cells, current therapies fail to reverse vascular remodeling, underscoring the urgent need for novel therapeutic strategies. Recent research has shifted focus towards intracellular organelles, specifically mitochondria and the endoplasmic reticulum (ER), as potential therapeutic targets. A key area of interest is mitochondria-associated membranes (MAMs), specialized contact sites between mitochondria and the ER that regulate essential cellular processes, including calcium homeostasis, ER stress signaling, autophagy, and insulin signaling. This review explores the emerging role of MAMs in the pathogenesis of PAH, detailing the molecular players involved in MAM formation and function. Emphasis is placed on identifying MAM-associated proteins that are dysregulated in PASMCs and PAECs, providing insights into their potential as novel therapeutic targets in PAH.
{"title":"Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension","authors":"Gauri Chaturvedi , Nandini Dubey , Pranav Panchbhai , Satnam Singh , Ravinder Singh , Upendra Baitha , Neeraj Parakh , Rajiv Narang , Harlokesh Narayan Yadav","doi":"10.1016/j.mito.2025.102094","DOIUrl":"10.1016/j.mito.2025.102094","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by hyperproliferation and remodeling of the pulmonary vasculature, primarily affecting pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). Although several pharmacological agents target the known signaling pathways in these cells, current therapies fail to reverse vascular remodeling, underscoring the urgent need for novel therapeutic strategies. Recent research has shifted focus towards intracellular organelles, specifically mitochondria and the endoplasmic reticulum (ER), as potential therapeutic targets. A key area of interest is mitochondria-associated membranes (MAMs), specialized contact sites between mitochondria and the ER that regulate essential cellular processes, including calcium homeostasis, ER stress signaling, autophagy, and insulin signaling. This review explores the emerging role of MAMs in the pathogenesis of PAH, detailing the molecular players involved in MAM formation and function. Emphasis is placed on identifying MAM-associated proteins that are dysregulated in PASMCs and PAECs, providing insights into their potential as novel therapeutic targets in PAH.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102094"},"PeriodicalIF":4.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505737","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 : 2025-11-05DOI: 10.1016/j.mito.2025.102095
Olatz Ugarteburu , Laia Farré-Tarrats , Gerard Muñoz-Pujol , María Unceta , Javier De Las Heras , Ainhoa Garcia-Ribes , Arantza Arza-Ruesga , Belén de la Morena , Gianluca Arauz-Garofalo , Marina Gay , Gloria Garrabou , Javier Corral , Marta Vilaseca , Antonia Ribes , Judit García-Villoria , Laura Gort , Frederic Tort
COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient’s tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV. Additionally, proteomic data in patient’s fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.
{"title":"Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome","authors":"Olatz Ugarteburu , Laia Farré-Tarrats , Gerard Muñoz-Pujol , María Unceta , Javier De Las Heras , Ainhoa Garcia-Ribes , Arantza Arza-Ruesga , Belén de la Morena , Gianluca Arauz-Garofalo , Marina Gay , Gloria Garrabou , Javier Corral , Marta Vilaseca , Antonia Ribes , Judit García-Villoria , Laura Gort , Frederic Tort","doi":"10.1016/j.mito.2025.102095","DOIUrl":"10.1016/j.mito.2025.102095","url":null,"abstract":"<div><div><em>COX4I1</em> gene encodes cytochrome <em>c</em> oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, <em>COX4I1</em> pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo <em>COX4I1</em> nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient’s tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.<!--> <!-->Additionally, proteomic data in patient’s fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102095"},"PeriodicalIF":4.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471539","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}
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.
{"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":4.5,"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}
The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE development from the earliest tool mitochondria targeted TALENs to the most recent base editing systems that can precisely convert C•G → T•A and A•T → G•C, we review mitoBEs. We describe the development of recent advancements in mitoBEs including the generation of second generation mitoBEs (mitoBEs v2), which have evidence to identify over 70 mouse mtDNA mutations comparable to human pathogenic variants. Notably, in order to incorporate circular RNA (circRNA) as a delivery vector the editing efficiency has been increased by over 82 %, without experimental evidence of off-target effects. Taking advantage of these gains in technology, these mouse models of mitochondrial diseases, including those associated with Leigh syndrome and LHN, are highly faithful. These models have also confirmed that these specific mtDNA variants have pathological phenotypic evaluations, and have compared to previous editing strategies, mitoBEs v2 have demonstrated improved specificity, stability and safety. We finally discuss the future of mitochondrial base editing and outline the ways it will move forward towards therapeutic potentials in the treatment of the mitochondrial disorders and also in precision medicine.
{"title":"The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential","authors":"Prathamesh Shelke , Sharon Tribhuvan , Ashish Kumar Agrahari , Reshu Saxena","doi":"10.1016/j.mito.2025.102093","DOIUrl":"10.1016/j.mito.2025.102093","url":null,"abstract":"<div><div>The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE development from the earliest tool mitochondria targeted TALENs to the most recent base editing systems that can precisely convert C•G → T•A and A•T → G•C, we review mitoBEs. We describe the development of recent advancements in mitoBEs including the generation of second generation mitoBEs (mitoBEs v2), which have evidence to identify over 70 mouse mtDNA mutations comparable to human pathogenic variants. Notably, in order to incorporate circular RNA (circRNA) as a delivery vector the editing efficiency has been increased by over 82 %, without experimental evidence of off-target effects. Taking advantage of these gains in technology, these mouse models of mitochondrial diseases, including those associated with Leigh syndrome and LHN, are highly faithful. These models have also confirmed that these specific mtDNA variants have pathological phenotypic evaluations, and have compared to previous editing strategies, mitoBEs v2 have demonstrated improved specificity, stability and safety. We finally discuss the future of mitochondrial base editing and outline the ways it will move forward towards therapeutic potentials in the treatment of the mitochondrial disorders and also in precision medicine.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102093"},"PeriodicalIF":4.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145418618","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 : 2025-10-28DOI: 10.1016/j.mito.2025.102092
Ali Jawad Akki , Shankargouda V Patil , Nilima Dongre , Prachi Parvatikar
MicroRNAs (miRNAs), small non-coding RNA molecules known for their gene regulatory functions, are increasingly recognized to target genes critical for mitochondrial function in hepatocellular carcinoma (HCC). By employing in silico analysis this research investigates the underexplored involvement of a network of microRNAs in regulating mitochondrial fission within the context of HCC. We constructed a novel regulatory network, identifying hsa-miR-138-5p as a central regulator targeting key mitochondrial genes. Furthermore, we identified druggable binding pockets on the transcription factors WDR5 and HNF4, which regulate hsa-miR-138-5p. Molecular docking studies demonstrated favorable binding affinities of FDA-approved HCC drugs (sorafenib, lenvatinib, and regorafenib) to these binding pockets, suggesting an off-target mechanism by which these drugs might influence mitochondrial function through the hsa-miR-138-5p pathway. These findings contribute to the growing understanding of miRNA-mediated regulation in HCC and offer a foundation for developing novel microRNA-targeting drugs to modulate mitochondrial dynamics to manage HCC progression.
{"title":"In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma","authors":"Ali Jawad Akki , Shankargouda V Patil , Nilima Dongre , Prachi Parvatikar","doi":"10.1016/j.mito.2025.102092","DOIUrl":"10.1016/j.mito.2025.102092","url":null,"abstract":"<div><div>MicroRNAs (miRNAs), small non-coding RNA molecules known for their gene regulatory functions, are increasingly recognized to target genes critical for mitochondrial function in hepatocellular carcinoma (HCC). By employing <em>in silico</em> analysis this research investigates the underexplored involvement of a network of microRNAs in regulating mitochondrial fission within the context of HCC. We constructed a novel regulatory network, identifying hsa-miR-138-5p as a central regulator targeting key mitochondrial genes. Furthermore, we identified druggable binding pockets on the transcription factors WDR5 and HNF4, which regulate hsa-miR-138-5p. Molecular docking studies demonstrated favorable binding affinities of FDA-approved HCC drugs (sorafenib, lenvatinib, and regorafenib) to these binding pockets, suggesting an off-target mechanism by which these drugs might influence mitochondrial function through the hsa-miR-138-5p pathway. These findings contribute to the growing understanding of miRNA-mediated regulation in HCC and offer a foundation for developing novel microRNA-targeting drugs to modulate mitochondrial dynamics to manage HCC progression.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102092"},"PeriodicalIF":4.5,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409461","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 : 2025-09-29DOI: 10.1016/j.mito.2025.102083
Anthony Stapon , Miguel Garcia-Diaz
Mitochondrial transcription is key for mitochondrial biogenesis, essential for both gene expression and mtDNA replication. Because of the difficulty of studying the process in vivo, studies of mitochondrial transcription have largely relied on in vitro approaches. Existing methods are based on incorporation of a radioactively labeled nucleotide to facilitate detection of the product while not perturbing the transcription reaction. However, they are difficult to use and cumbersome, preventing their widespread utilization. Here we report a new non-radioactive approach for the in vitro study of mitochondrial transcription that relies on the bio-orthogonal click chemistry reaction, utilizing click-chemistry ready azide-labeled UTP in the mitochondrial transcription system. Our approach recapitulates results obtained using radioactive methods and can be carried out using the reaction conditions typically used for in vitro radioactivity assays.
{"title":"Mitochondrial Transcription: A click-chemistry derived detection methodology forgoing the use of radiation in in vitro analyses","authors":"Anthony Stapon , Miguel Garcia-Diaz","doi":"10.1016/j.mito.2025.102083","DOIUrl":"10.1016/j.mito.2025.102083","url":null,"abstract":"<div><div>Mitochondrial transcription is key for mitochondrial biogenesis, essential for both gene expression and mtDNA replication. Because of the difficulty of studying the process <em>in vivo</em>, studies of mitochondrial transcription have largely relied on <em>in vitro</em> approaches. Existing methods are based on incorporation of a radioactively labeled nucleotide to facilitate detection of the product while not perturbing the transcription reaction. However, they are difficult to use and cumbersome, preventing their widespread utilization. Here we report a new non-radioactive approach for the <em>in vitro</em> study of mitochondrial transcription that relies on the bio-orthogonal click chemistry reaction, utilizing click-chemistry ready azide-labeled UTP in the mitochondrial transcription system. Our approach recapitulates results obtained using radioactive methods and can be carried out using the reaction conditions typically used for <em>in vitro</em> radioactivity assays.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102083"},"PeriodicalIF":4.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206883","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 : 2025-09-28DOI: 10.1016/j.mito.2025.102082
Reiji Tokito , Kosei Oishi , Tomoya Sugiyama , Yusuke Fujisawa , Fujino Kuba , Kaito Yoshida , Kaoru Yoshida , Manabu Yoshida , Yoichiro Tanaka , Taku Amo , Noritaka Yamaguchi , Taishin Akiyama , Yuji Imai , Kazuto Yoshimi , Tsuyoshi Koide , Yasuyuki Kurihara
COXFA4L3 is a testis-specific cytochrome c oxidase subunit that enhances mitochondrial complex IV activity during spermatogenesis. From the analysis of Coxfa4l3 knockout mice, the isoform switch from COXFA4 to COXFA4L3 may increase the potential COX activity, although this activity does not appear in the testis. This latent enhancement becomes evident in sperm, where COXFA4L3 promotes higher respiratory capacity, increasing sperm motility and ATP production. These findings indicate that COXFA4L3 is a key regulator of mitochondrial energy metabolism and may provide insights into the mechanisms underlying male infertility.
{"title":"COXFA4L3 enhances mitochondrial complex IV function to boost ATP synthesis and drive sperm motility","authors":"Reiji Tokito , Kosei Oishi , Tomoya Sugiyama , Yusuke Fujisawa , Fujino Kuba , Kaito Yoshida , Kaoru Yoshida , Manabu Yoshida , Yoichiro Tanaka , Taku Amo , Noritaka Yamaguchi , Taishin Akiyama , Yuji Imai , Kazuto Yoshimi , Tsuyoshi Koide , Yasuyuki Kurihara","doi":"10.1016/j.mito.2025.102082","DOIUrl":"10.1016/j.mito.2025.102082","url":null,"abstract":"<div><div>COXFA4L3 is a testis-specific cytochrome <em>c</em> oxidase subunit that enhances mitochondrial complex IV activity during spermatogenesis. From the analysis of <em>Coxfa4l3</em> knockout mice, the isoform switch from COXFA4 to COXFA4L3 may increase the potential COX activity, although this activity does not appear in the testis. This latent enhancement becomes evident in sperm, where COXFA4L3 promotes higher respiratory capacity, increasing sperm motility and ATP production. These findings indicate that COXFA4L3 is a key regulator of mitochondrial energy metabolism and may provide insights into the mechanisms underlying male infertility.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102082"},"PeriodicalIF":4.5,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200210","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 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}
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