Mitochondrion最新文献_第3页

Dysregulation of RUNX1 isoforms drives mitochondrial defects during neural differentiation in down syndrome RUNX1亚型的失调驱动唐氏综合征神经分化过程中的线粒体缺陷

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-12-03 DOI: 10.1016/j.mito.2025.102108

Yan-na Liu , Qin Cai , Ke-yi Li , Wen-xiu Li , Guang He , Fanyi Zeng , Jing-bin Yan

Down syndrome (DS) is distinguished by neurodevelopmental abnormalities, with mitochondrial dysfunction. The Runt-related transcription factor 1 (RUNX1) gene, located within the Down Syndrome Critical Region (DSCR), is known to encode three major isoforms (RUNX1a, RUNX1b and RUNX1c) that play essential roles in neurodevelopmental processes. Our previous research demonstrated that RUNX1 overexpression induces mitochondrial dysfunction in DS-induced pluripotent stem cells (DS-iPSCs). However, the functional impacts of altered expression levels of these RUNX1 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 RUNX1b and RUNX1c transcription levels were consistently observed in DS peripheral blood mononuclear cells, iPSCs and NSCs. Overexpression of RUNX1c in NSCs not only suppressed RUNX1a 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 RUNX1c not only reduced ROS levels but also restored the impaired oxidative phosphorylation in DS-NSCs. Furthermore, our findings revealed that the downregulation of LINC01426, a long non-coding RNA located adjacent to RUNX1, during the neural differentiation of DS-iPSCs resulted in the overexpression of RUNX1c, owing to the reduced interaction with the splicing factor. These findings collectively indicate that the LINC01426-mediated activation of RUNX1c isoforms contributes to mitochondrial dysfunction and morphological abnormalities, ultimately leading to impaired neural differentiation in DS.

唐氏综合征（DS）以神经发育异常和线粒体功能障碍为特征。runt相关转录因子1 （RUNX1）基因位于唐氏综合征关键区（DSCR），已知编码三种主要亚型（RUNX1a， RUNX1b和RUNX1c），在神经发育过程中发挥重要作用。我们之前的研究表明，RUNX1过表达可诱导DS-iPSCs的线粒体功能障碍。然而，这些RUNX1亚型表达水平的改变对线粒体功能的功能影响，以及它们在神经干细胞（NSCs）中表达的调控机制，仍有待阐明。在这项研究中，我们的研究结果显示，DS-NSCs表现出氧化磷酸化减少，线粒体数量增加，结构损伤。RUNX1b和RUNX1c转录水平在DS外周血单个核细胞、iPSCs和NSCs中一致升高。NSCs中RUNX1c的过表达不仅抑制了RUNX1a的表达，还导致线粒体ATP生成速率大幅降低，活性氧（ROS）水平显著升高。相比之下，RUNX1c的下调不仅降低了ROS水平，还恢复了DS-NSCs中受损的氧化磷酸化。此外，我们的研究结果表明，在DS-iPSCs的神经分化过程中，位于RUNX1附近的长链非编码RNA LINC01426的下调导致RUNX1c过表达，这是由于与剪接因子的相互作用减少。这些发现共同表明，linc01426介导的RUNX1c亚型激活有助于线粒体功能障碍和形态异常，最终导致DS的神经分化受损。

{"title":"Dysregulation of RUNX1 isoforms drives mitochondrial defects during neural differentiation in down syndrome","authors":"Yan-na Liu , Qin Cai , Ke-yi Li , Wen-xiu Li , Guang He , Fanyi Zeng , 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":"2025-12-03","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}

引用次数: 0

The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly 线粒体蛋白TMEM177微调哺乳动物细胞色素c氧化酶组装。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-16 DOI: 10.1016/j.mito.2025.102099

Jakob D. Busch , Thomas Schöndorf , Dusanka Milenkovic , Xinping Li , Rolf Wibom , Joana F. Silva-Rodrigues , Roberta Filograna , Camilla Koolmeister , Nils-Göran Larsson , Diana Rubalcava-Gracia

The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.

线粒体细胞色素c氧化酶（COX，复合体IV）是一种多亚基蛋白复合体，通过将氧还原为水并同时泵送质子以实现氧化磷酸化（OXPHOS），在细胞呼吸中起着至关重要的作用。因此，其组装缺陷可直接影响细胞能量稳态。COX20是核心亚基COX2的重要伴侣。在人类培养细胞中，TMEM177被发现稳定COX20并维持平衡的COX2水平。在小鼠中，TMEM177也被鉴定为线粒体核糖体的相互作用物。为了了解TMEM177在体内的功能，我们制造了TMEM177敲除小鼠。在这里，我们分析了TMEM177丢失如何影响线粒体基因表达，以及OXPHOS复合物的活性和组装。我们发现一小部分基因敲除小鼠在围产期死亡，而存活的基因敲除小鼠往往体重增加较少。TMEM177缺失适度降低了COX20水平，但保留了OXPHOS复合物。此外，Tmem177和Surf1双敲除小鼠出生时无症状。总之，TMEM177通过稳定体内COX20来微调复合物IV的组装。我们的发现完善了目前哺乳动物复合体IV组装的模型。

{"title":"The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly","authors":"Jakob D. Busch , Thomas Schöndorf , Dusanka Milenkovic , Xinping Li , Rolf Wibom , Joana F. Silva-Rodrigues , Roberta Filograna , Camilla Koolmeister , Nils-Göran Larsson , Diana Rubalcava-Gracia","doi":"10.1016/j.mito.2025.102099","DOIUrl":"10.1016/j.mito.2025.102099","url":null,"abstract":"<div><div>The mitochondrial cytochrome <em>c</em> oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 <em>in vivo</em>, we generated <em>Tmem177</em> knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, <em>Tmem177</em> and <em>Surf1</em> double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 <em>in vivo</em>. Our findings refine the current model of complex IV assembly in mammals.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"86 ","pages":"Article 102099"},"PeriodicalIF":4.5,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549301","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}

引用次数: 0

A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder 自闭症谱系障碍核心症状的3击代谢信号模型

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-14 DOI: 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.

描述了自闭症谱系障碍（ASD）病因的3击代谢信号模型。ASD的3项要求是：1)遗传一种基因型，使线粒体和/或eap刺激的细胞内钙信号对环境变化敏感；2)早期暴露于激活细胞危险反应（CDR）代谢特征的环境触发因素；3)从妊娠前三个月晚期到生命最初18-36 个月的关键神经发育窗口期，反复或持续暴露于CDR激活触发因素至少3-6个 个月。与ASD风险增加相关的三种突变在功能上可分别归类为CDR的引物、触发物和放大物。由于CDR是由代谢信号维持的，这个新模型为理解ASD的不同特征是如何联系在一起创造了一个统一的知识框架。苯丙酮尿症（PKU）的例子表明，即使具有非常强的遗传倾向的疾病也可以遵循这种3-hit发育模式，并且仍然可以使用代谢信号传导原理进行治疗。由于第二和第三点是可以修改的，因此该模型预测，如果高危儿童能够在症状出现之前得到诊断和治疗，那么多达40- 50% %的这些儿童可能永远不会发展为ASD，如果在症状出现后得到诊断，那么最致残的核心症状可以显著减少。总结。描述了自闭症谱系障碍的三击发育模型。系统生物学的新方法已经确定了线粒体功能和代谢的变化模式，这是ASD核心症状的基础。细胞危险反应（CDR）的代谢特征，由atp相关嘌呤能信号异常维持，已成为迄今为止研究的ASD的遗传和环境原因的共同特征。

{"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}

引用次数: 0

Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation 钙胁迫下线粒体活力的评估：线粒体移植的见解。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-12 DOI: 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.

线粒体移植已成为一种很有前途的缺血再灌注损伤心脏保护策略，旨在通过向受损组织输送健康的线粒体来恢复生物能量功能。然而，关于线粒体是否能够在细胞摄取前暴露于富含钙的细胞外环境（如血液）中存活，存在相互矛盾的报道。解决这个问题对于推进线粒体在临床环境中的治疗用途至关重要。将L6大鼠骨骼肌细胞分离的线粒体与生理性（1.3  mM）、亚生理性（0.65  mM）和超生理性（2.6  mM）浓度的钙孵育。使用MitoTracker™Red FM荧光评估线粒体膜电位，使用基于阻抗的Coulter计数器分析在12小时的时间过程中评估结构完整性。暴露于1.3  mM钙的线粒体在12 小时内保留了90- 95% %的膜电位，而2.6  mM钙导致功能和完整性的逐渐丧失，接近冻融对照组的水平。Coulter计数器测量显示，在所有钙处理组中，线粒体损失比单独的荧光分析更广泛，这表明基于染料的方法可能低估了结构损伤。尽管如此，在生理上相关的钙水平下，相当一部分线粒体在结构和功能上保持完整。这些发现表明，相当数量的线粒体在暴露于接近血液中的细胞外钙浓度后可以保持膜电位和结构完整性。这支持了冠状动脉内线粒体移植的可行性，并强调了进一步的体内研究的必要性，以优化线粒体在富钙环境中的存活和疗效。

{"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}

引用次数: 0

Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy 静脉线粒体移植作为扩张型心肌病的辅助治疗。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-11 DOI: 10.1016/j.mito.2025.102097

Tuğba Varlik , Didem Algan , Öner Sönmez , Keshav K. Singh , Öner Ülger , Gökhan Burçin Kubat , Jørgen Koch , Zeki Yilmaz

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.

扩张型心肌病（DCM）是各种动物中最常见的心肌疾病之一。DCM的潜在原因是复杂的，通常涉及多种促成机制。线粒体功能障碍已被确定为心肌细胞凋亡进展的关键因素。我们研究了健康线粒体的移植是否通过增强心肌细胞的收缩功能来改善心脏功能。一只患有心肌病的6岁狗接受了来自健康供体的血小板来源的活线粒体作为辅助治疗，并进行了标准的医疗管理。从血小板中分离线粒体，并以81,125 μg/mL的剂量单次静脉给药。该程序是在连续心电图和生命体征监测下进行的。采用常规超声心动图和二维散斑跟踪成像，多次间隔评估心室收缩功能。我们的研究显示，早在线粒体移植后两小时，收缩性能就有了显著改善，收缩能力的增强持续了24 h。这些研究表明，线粒体移植可能为心功能障碍的常规治疗提供一种有希望的干预或辅助手段。本报告提出了第一例记录在案的静脉线粒体移植在犬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}

引用次数: 0

Mitochondrial-ER crosstalk: An emerging mechanism in the pathophysiology of pulmonary arterial hypertension 线粒体-内质网串扰：肺动脉高压病理生理的新机制。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-10 DOI: 10.1016/j.mito.2025.102094

Gauri Chaturvedi , Nandini Dubey , Pranav Panchbhai , Satnam Singh , Ravinder Singh , Upendra Baitha , Neeraj Parakh , Rajiv Narang , Harlokesh Narayan Yadav

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.

肺动脉高压（PAH）是一种以肺血管增生和重构为特征的进行性致命疾病，主要影响肺动脉平滑肌细胞（PASMCs）和肺动脉内皮细胞（PAECs）。尽管一些药物靶向这些细胞中的已知信号通路，但目前的治疗方法无法逆转血管重构，这表明迫切需要新的治疗策略。最近的研究已将焦点转移到细胞内细胞器，特别是线粒体和内质网（ER），作为潜在的治疗靶点。我们感兴趣的一个关键领域是线粒体相关膜（MAMs），线粒体和内质网之间的特殊接触点，调节基本的细胞过程，包括钙稳态、内质网应激信号、自噬和胰岛素信号。本文探讨了MAM在PAH发病机制中的新作用，详细介绍了参与MAM形成和功能的分子参与者。重点是鉴定在PASMCs和PAECs中失调的mam相关蛋白，从而深入了解它们作为PAH新治疗靶点的潜力。

{"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}

引用次数: 0

Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome 由于cox4i1深层内含子和新生变异导致复合物IV缺乏导致进行性运动障碍和leigh综合征。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-05 DOI: 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.

COX4I1基因编码细胞色素c氧化酶亚基4亚型1，参与线粒体呼吸链复合体IV的早期组装阶段。迄今为止，仅在少数病例中报道了COX4I1致病性变异，每种变异均表现出异质性临床表型和有限的功能数据。在这里，我们描述了第四例报告的与人类疾病相关的COX4I1缺乏症，扩大了这种罕见线粒体疾病的表型和遗传谱，并提供了新的临床、分子和功能数据。本文报道的个体表现为运动技能进行性恶化，智力残疾和与Leigh综合征相符的脑成像异常。结合短读和长读下一代测序的遗传学研究发现，该患者中存在一种特殊的基因组合，其中包含一个从头开始的COX4I1无义替换和一个遗传的深内含子变异（c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]）。在患者组织和瞬时转染细胞系中进行的功能研究表明，所鉴定的变异主要通过靶向COX4I1蛋白水平来发挥其致病作用，从而损害复合体IV的正常组装和活性。此外，患者成纤维细胞的蛋白质组学数据表明，潜在的病理机制不仅涉及复合体IV功能的调节，还涉及线粒体蛋白水平的调节。总之，我们的研究结果阐明了与COX4I1缺乏症相关的一些主要临床特征以及与该疾病发病机制相关的分子机制。

{"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}

引用次数: 0

Mitochondrial quality control in exercise-mitigated muscular atrophy. 运动缓解性肌萎缩的线粒体质量控制。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-11-01 Epub Date: 2025-07-28 DOI: 10.1016/j.mito.2025.102074

Jingcheng Fan, Xin Wen, Xuemei Duan, Xinyi Zhu, Jianzheng Bai, Tan Zhang

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.

肌肉萎缩是肌肉质量的损失，给患者和社会带来了巨大的负担。蛋白质降解增加、蛋白质合成减少、炎症反应、氧化应激和线粒体功能障碍是肌萎缩的危险因素。线粒体质量控制（MQC）过程维持线粒体健康，这是维持骨骼肌结构和功能完整性所必需的。值得注意的是，人们普遍认为有规律的运动能显著改善肌肉萎缩。从机制上讲，运动通过MQC增强线粒体功能，并减轻肌肉萎缩。然而，MQC在运动减弱性肌萎缩中的作用和分子机制尚未完全阐明。在此，我们回顾了MQC在肌萎缩中的相关知识，重点关注MQC在运动介导的抗萎缩作用，这可能有助于通过靶向线粒体预防和治疗肌萎缩。

引用次数: 0

The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential 线粒体碱基编辑的发展前景：精度、建模和治疗潜力方面的进步

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-10-30 DOI: 10.1016/j.mito.2025.102093

Prathamesh Shelke , Sharon Tribhuvan , Ashish Kumar Agrahari , Reshu Saxena

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.

线粒体碱基编辑器（mitoBEs）的最新发展已经迎来了一个变革的时代，克服了线粒体遗传学领域一些长期存在的局限性。通过密切追踪mitoBE的发展，从最早的工具线粒体靶向TALENs到最近的碱基编辑系统，可以精确地转换C•G→T•A和A•T→G•C，我们回顾了mitoBE。我们描述了mitoBEs的最新进展，包括第二代mitoBEs (mitoBEs v2)，它有证据表明超过70种小鼠mtDNA突变与人类致病变异相当。值得注意的是，为了将环状RNA （circRNA）作为传递载体，编辑效率提高了82%以上，没有实验证据表明脱靶效应。利用这些技术上的进步，这些线粒体疾病的小鼠模型，包括那些与Leigh综合征和LHN相关的疾病，是高度可靠的。这些模型也证实了这些特定的mtDNA变体具有病理表型评估，并且与之前的编辑策略相比，mitoBEs v2显示出更高的特异性、稳定性和安全性。我们最后讨论了线粒体碱基编辑的未来，并概述了它在线粒体疾病治疗和精准医学方面的治疗潜力。

{"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}

引用次数: 0

In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma 影响肝细胞癌线粒体分裂的MicroRNA调控网络的计算机分析。

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-10-28 DOI: 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.

MicroRNAs （miRNAs）是一种以基因调控功能而闻名的非编码小RNA分子，越来越多地被认为是肝细胞癌（HCC）中对线粒体功能至关重要的基因。通过采用计算机分析，本研究调查了在HCC背景下，microrna网络在调节线粒体裂变中的未被充分探索的参与。我们构建了一个新的调控网络，确定了hsa-miR-138-5p是一个针对关键线粒体基因的中央调控因子。此外，我们在调节hsa-miR-138-5p的转录因子WDR5和HNF4上发现了可药物结合袋。分子对接研究表明，fda批准的HCC药物（sorafenib， lenvatinib和regorafenib）与这些结合口袋具有良好的结合亲和力，提示这些药物可能通过hsa-miR-138-5p途径影响线粒体功能的脱靶机制。这些发现有助于加深对mirna介导的HCC调控的理解，并为开发新的靶向mirna的药物来调节线粒体动力学以控制HCC进展提供基础。

{"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}

引用次数: 0