Mitochondrion最新文献

{"title":"Aagab-driven SHIP2 degradation rescues mitochondrial dysfunction in hypoxic-ischemic encephalopathy","authors":"Jinli Han ,&nbsp;Lu He ,&nbsp;Ling Chen ,&nbsp;Bin Wen ,&nbsp;Jinglu Ji","doi":"10.1016/j.mito.2025.102109","DOIUrl":"10.1016/j.mito.2025.102109","url":null,"abstract":"<div><div>Neonatal hypoxic–ischemic encephalopathy (HIE), a central nervous system disorder caused by oxygen deprivation and reduced cerebral blood flow, involves complex mechanisms including mitochondrial oxidative stress and neuronal injury. The Rab-like GTPase domain-containing protein Aagab has been linked to neuronal regulation by modulating neural precursor cell expressed, developmentally down-regulated protein 4-1 (NEDD4-1)–mediated ubiquitination and degradation of Src homology 2 domain–containing inositol 5-phosphatase 2 (SHIP2). In this study, we investigated the contribution of the Aagab–NEDD4-1–SHIP2 axis to hypoxic-ischemic encephalopathy (HIE) and its influence on mitochondrial oxidative stress. Multi-omics analyses of publicly available RNA sequencing and proteomic datasets from HIE and control rat brain tissues identified SHIP2 as a significantly upregulated gene strongly associated with oxidative stress pathways. In an oxygen–glucose deprivation (OGD) neuronal model, lentiviral knockdown of SHIP2 enhanced neuronal viability, reduced reactive oxygen species production, and restored mitochondrial membrane potential. <em>In vivo</em>, tail-vein delivery of lentiviral vectors to silence SHIP2 in neonatal rat HIE models led to marked improvements in neurological outcomes, including reduced escape latency in the Morris water maze, increased success rates in the ladder-rung test, and diminished brain lesion area. Mechanistic assays demonstrated that Aagab overexpression increased NEDD4-1 levels, promoted SHIP2 ubiquitination, and accelerated its degradation, whereas NEDD4-1 knockdown reversed these effects. Collectively, these findings indicate that Aagab facilitates NEDD4-1–mediated SHIP2 ubiquitination and degradation, thereby alleviating mitochondrial oxidative stress and mitigating HIE-associated neuronal injury. The Aagab–NEDD4-1–SHIP2 regulatory axis may represent a promising molecular target for therapeutic intervention in HIE.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102109"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum cell-free mitochondrial DNA under a highly standardized and controlled stress induction","authors":"Benedict Herhaus ,&nbsp;Carina Daubermann ,&nbsp;Elmo W.I. Neuberger ,&nbsp;Perikles Simon ,&nbsp;Katja Petrowski","doi":"10.1016/j.mito.2026.102113","DOIUrl":"10.1016/j.mito.2026.102113","url":null,"abstract":"<div><div>Cell-free mitochondrial DNA (ccf-mtDNA) is increasingly recognized as a biomarker of stress-related mitochondrial dysfunction. Acute psychological stress may induce ccf-mtDNA release, underscoring its potential role in stress physiology and adaptation. To further investigate this relationship, the present study examined acute stress-induced ccf-mtDNA dynamics in a controlled experimental setting. Twenty-seven healthy males (mean age: 23.78 ± 3.90 years) underwent both the Trier Social Stress Test (psychological stressor) and a resting condition. The kinetics of serum cell-free mitochondrial DNA (ccf-mtDNA) and serum cortisol were measured before and at 8 time points up to 105 min after the two stress conditions. After the TSST, ccf-mtDNA showed significant transient increases at +20 and +75 min, whereas cortisol exhibited the expected robust stress response. Our findings suggest that acute psychological stress can induce transient and heterogeneous changes in serum ccf-mtDNA, though these dynamics appear more modest and delayed than cortisol responses. Variability across studies underscores the need for standardized protocols and further research to clarify the mechanisms and moderators of ccf-mtDNA release under stress.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102113"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146063954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron","authors":"Svetlana Pecheritsyna ,&nbsp;Melisa Emel Ermert ,&nbsp;Emina Podhumljak ,&nbsp;Bas Pennings ,&nbsp;Ruth Zondag ,&nbsp;Eligio F Iannetti ,&nbsp;Herma Renkema ,&nbsp;Jan Smeitink","doi":"10.1016/j.mito.2026.102112","DOIUrl":"10.1016/j.mito.2026.102112","url":null,"abstract":"<div><div>Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary human skin fibroblasts (PHSF) to ferroptosis, and the role of iron in this cell death mechanism. To address this, we investigated sensitivity to ferroptosis inducers, the effects of iron supplementation, and intracellular iron pools. The selectivity of PMD fibroblasts ferroptotic cell death was found to be more pronounced with class 1 ferroptosis inducers (FINs) that deplete GSH than upon direct GPX4 inhibitors. Notably, exogenous iron discriminatory triggered ferroptosis in patient fibroblasts and enhanced BSO-induced cell death in both patient and control cells. Further study revealed elevated basal levels of labile iron in patient fibroblasts, but mRNA analysis of iron-regulating genes did not reveal major expression differences. These findings suggest that increased labile iron predisposes PMD fibroblasts to ferroptosis. Complementation of defective OXPHOS restored ferroptosis sensitivity and LIP levels in a cell line with an NDUFS7 mutation, indicating a functional relationship caused by OXPHOS deficiency.</div><div>Further understanding this interplay may provide insights into therapeutic strategies targeting iron homeostasis to mitigate ferroptotic cell death in PMDs.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102112"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of RUNX1 isoforms drives mitochondrial defects during neural differentiation in down syndrome","authors":"Yan-na Liu ,&nbsp;Qin Cai ,&nbsp;Ke-yi Li ,&nbsp;Wen-xiu Li ,&nbsp;Guang He ,&nbsp;Fanyi Zeng ,&nbsp;Jing-bin Yan","doi":"10.1016/j.mito.2025.102108","DOIUrl":"10.1016/j.mito.2025.102108","url":null,"abstract":"<div><div>Down syndrome (DS) is distinguished by neurodevelopmental abnormalities, with mitochondrial dysfunction. The Runt-related transcription factor 1 (<em>RUNX1</em>) gene, located within the Down Syndrome Critical Region (DSCR), is known to encode three major isoforms (<em>RUNX1a</em>, <em>RUNX1b</em> and <em>RUNX1c</em>) that play essential roles in neurodevelopmental processes. Our previous research demonstrated that <em>RUNX1</em> overexpression induces mitochondrial dysfunction in DS-induced pluripotent stem cells (DS-iPSCs). However, the functional impacts of altered expression levels of these <em>RUNX1</em> isoforms on mitochondrial function, as well as the regulatory mechanisms governing their expression in neural stem cells (NSCs), remain to be elucidated. In this study, our results revealed that DS-NSCs exhibited reduced oxidative phosphorylation and an increased number of mitochondria with structural damage. Consistently elevated <em>RUNX1b and RUNX1c</em> transcription levels were consistently observed in DS peripheral blood mononuclear cells, iPSCs and NSCs. Overexpression of <em>RUNX1c</em> in NSCs not only suppressed <em>RUNX1a</em> expression but also resulted in a substantial decrease in mitochondrial ATP production rate and a significant elevation in reactive oxygen species (ROS) levels. In contrast, knockdown of <em>RUNX1c</em> not only reduced ROS levels but also restored the impaired oxidative phosphorylation in DS-NSCs. Furthermore, our findings revealed that the downregulation of <em>LINC01426</em>, a long non-coding RNA located adjacent to <em>RUNX1</em>, during the neural differentiation of DS-iPSCs resulted in the overexpression of <em>RUNX1c</em>, owing to the reduced interaction with the splicing factor. These findings collectively indicate that the <em>LINC01426</em>-mediated activation of <em>RUNX1c</em> isoforms contributes to mitochondrial dysfunction and morphological abnormalities, ultimately leading to impaired neural differentiation in DS.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102108"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration","authors":"Cunhui Pan ,&nbsp;Ruowei Zhu ,&nbsp;Xi Huang ,&nbsp;Haolin Duan ,&nbsp;Tenghui Wu ,&nbsp;Xiaole Wang ,&nbsp;Ying Ding ,&nbsp;Chen Chen ,&nbsp;Fang He ,&nbsp;Jing Peng ,&nbsp;Fei Yin ,&nbsp;Xiaoting Lou ,&nbsp;Li Yang","doi":"10.1016/j.mito.2025.102110","DOIUrl":"10.1016/j.mito.2025.102110","url":null,"abstract":"<div><div>Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene <em>FOXRED1</em>, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous <em>FOXRED1</em> mutations (c.850T&gt;C (p.C284R)/c.1054C&gt;T (p.R352W) and c.1054C&gt;T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD⁺/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. <em>FOXRED1</em> mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD⁺/NADH imbalance. Niacin restored the NAD⁺/NADH ratio <em>in vitro</em>, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102110"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential","authors":"Hélène Calais,&nbsp;Giulia Bertolin","doi":"10.1016/j.mito.2025.102107","DOIUrl":"10.1016/j.mito.2025.102107","url":null,"abstract":"<div><div>Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102107"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria transfer from myocytes to endothelial cells promotes angiogenesis in skeletal muscle","authors":"Yu-Feng Long ,&nbsp;Ai-Jun Huang ,&nbsp;Shuo Tang ,&nbsp;Zhen Xu ,&nbsp;Ming-Yue Wu ,&nbsp;Kai Liu ,&nbsp;Ze-Cai Chen ,&nbsp;Lei Qin ,&nbsp;Bing-Yang Dai ,&nbsp;Cheng Dong ,&nbsp;Wing-Hoi Cheung ,&nbsp;Xin-Luan Wang ,&nbsp;Da-Zhi Yang","doi":"10.1016/j.mito.2026.102116","DOIUrl":"10.1016/j.mito.2026.102116","url":null,"abstract":"<div><div>Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endothelial cells. Using <em>in vitro</em> 2D and 3D coculture systems, combined with protein-level and functional analyses, we show that mitochondria are transferred via extracellular vesicles in a Rab7-dependent and cellular connection-independent manner. Connexin 43 (CX43) inhibition downregulating Growth-Associated Protein 43 (GAP43) but enhances mitochondria transfer, accompanied by increasing Rab7. Transferred mitochondria promote endothelial cells proliferation, migration, ATP production, and angiogenesis, which could be the key processes in preserving vascular integrity and muscle function. Our study indicated that the aging-associated decline in CX43 and mitochondrial quality exacerbates muscle atrophy by facilitating the transfer of dysfunctional mitochondria. These findings uncover a novel mechanism of muscle–vessel communication and highlight mitochondria transfer as a potential therapeutic target for aging-related muscular and vascular deterioration.</div><div>New and Noteworthy.</div><div>Mitochondria transfer is a way for cell communication. However, mitochondria transfer between myocyte and endothelial cell remains unknown. Here, we demonstrates that mitochondria transfer occurs between myocytes and endothelial cells. Interestingly, inhibition of CX43 leads to a decrease in GAP43 expression, while simultaneously upregulating Rab7 and enhancing mitochondria transfer from myocytes to endothelial cells. Furthermore, we reveal that Rab7-induced mechanism mediates the transfer of both functional and impaired mitochondria from myocytes to endothelial cells.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"87 ","pages":"Article 102116"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma","authors":"Ali Jawad Akki ,&nbsp;Shankargouda V Patil ,&nbsp;Nilima Dongre ,&nbsp;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":"2026-01-01","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}

{"title":"Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome","authors":"Olatz Ugarteburu ,&nbsp;Laia Farré-Tarrats ,&nbsp;Gerard Muñoz-Pujol ,&nbsp;María Unceta ,&nbsp;Javier De Las Heras ,&nbsp;Ainhoa Garcia-Ribes ,&nbsp;Arantza Arza-Ruesga ,&nbsp;Belén de la Morena ,&nbsp;Gianluca Arauz-Garofalo ,&nbsp;Marina Gay ,&nbsp;Gloria Garrabou ,&nbsp;Javier Corral ,&nbsp;Marta Vilaseca ,&nbsp;Antonia Ribes ,&nbsp;Judit García-Villoria ,&nbsp;Laura Gort ,&nbsp;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&gt;T];[73+1511A&gt;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":"2026-01-01","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}

{"title":"Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation","authors":"Melody Toosky ,&nbsp;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":"2026-01-01","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}