Pub Date : 2025-11-14DOI: 10.1016/j.mito.2025.102096
Robert K. Naviaux
A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracellular calcium signaling to environmental change, 2) early exposure to environmental triggers that activate the metabolic features of the cell danger response (CDR), and 3) recurrent or persistent exposure to CDR-activating triggers for at least 3–6 months during the critical neurodevelopmental window from the late 1st trimester of pregnancy to the first 18–36 months of life. The three hits associated with an increased risk of ASD can be functionally classified as primers, triggers, and amplifiers of the CDR, respectively. Since the CDR is maintained by metabolic signaling, this new model creates a unified intellectual framework for understanding how the diverse features of ASD are connected. The example of phenylketonuria (PKU) is given to show that even disorders with very strong genetic predispositions can follow this 3-hit developmental paradigm and still be treatable using the principles of metabolic signaling. Since the 2nd and 3rd hits are modifiable, this model predicts that if the children at greatest risk can be diagnosed and treated before symptoms occur, some of these children may never develop ASD, and if diagnosed after symptoms occur, the core symptoms that are most disabling can be decreased significantly.
{"title":"A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder","authors":"Robert K. Naviaux","doi":"10.1016/j.mito.2025.102096","DOIUrl":"10.1016/j.mito.2025.102096","url":null,"abstract":"<div><div>A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracellular calcium signaling to environmental change, 2) early exposure to environmental triggers that activate the metabolic features of the cell danger response (CDR), and 3) recurrent or persistent exposure to CDR-activating triggers for at least 3–6 months during the critical neurodevelopmental window from the late 1st trimester of pregnancy to the first 18–36 months of life. The three hits associated with an increased risk of ASD can be functionally classified as primers, triggers, and amplifiers of the CDR, respectively. Since the CDR is maintained by metabolic signaling, this new model creates a unified intellectual framework for understanding how the diverse features of ASD are connected. The example of phenylketonuria (PKU) is given to show that even disorders with very strong genetic predispositions can follow this 3-hit developmental paradigm and still be treatable using the principles of metabolic signaling. Since the 2nd and 3rd hits are modifiable, this model predicts that if the children at greatest risk can be diagnosed and treated before symptoms occur, some of these children may never develop ASD, and if diagnosed after symptoms occur, the core symptoms that are most disabling can be decreased significantly.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102096"},"PeriodicalIF":4.5,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534640","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 : 2025-11-12DOI: 10.1016/j.mito.2025.102098
Melody Toosky , Arash Kheradvar
Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia–reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings.
Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3 mM), sub-physiologic (0.65 mM), and supraphysiologic (2.6 mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course.
Mitochondria exposed to 1.3 mM calcium retained 90–95 % membrane potential by 12 h, while 2.6 mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels.
These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further in vivo studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.
{"title":"Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation","authors":"Melody Toosky , Arash Kheradvar","doi":"10.1016/j.mito.2025.102098","DOIUrl":"10.1016/j.mito.2025.102098","url":null,"abstract":"<div><div>Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia–reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings.</div><div>Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3 mM), sub-physiologic (0.65 mM), and supraphysiologic (2.6 mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course.</div><div>Mitochondria exposed to 1.3 mM calcium retained 90–95 % membrane potential by 12 h, while 2.6 mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels.</div><div>These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further <em>in vivo</em> studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102098"},"PeriodicalIF":4.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523917","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}
Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.
{"title":"Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy","authors":"Tuğba Varlik , Didem Algan , Öner Sönmez , Keshav K. Singh , Öner Ülger , Gökhan Burçin Kubat , Jørgen Koch , Zeki Yilmaz","doi":"10.1016/j.mito.2025.102097","DOIUrl":"10.1016/j.mito.2025.102097","url":null,"abstract":"<div><div>Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102097"},"PeriodicalIF":4.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513357","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}
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}
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