Mitochondrion最新文献_第7页

Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway 抑制TRIM63表达可通过调节PPARα/PGC-1α通路减轻呼吸机诱导的膈功能障碍。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-04 DOI: 10.1016/j.mito.2025.102025

Jun Liu , Yuhan Chen , Dong Han , Ming Huang

Background

Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient.

Objectives

The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function.

Methods

Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated.

Results

Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission.

Conclusions

The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.

背景：呼吸机诱发的膈肌功能障碍（VIDD）显著影响危重患者的预后，已引起人们的广泛关注。Tripartite motif-containing protein 63 （TRIM63）在肌肉蛋白降解和肌肉质量调节中起关键作用。其过表达与VIDD密切相关；然而，关于TRIM63在这一病理过程中的具体作用的数据仍然不足。目的：本研究旨在阐明TRIM63在VIDD中的作用，并评估TRIM63-过氧化物酶体增殖物激活受体α (PPARα)/PPAR γ辅激活因子（PGC-1α）通路与线粒体功能的相关性。方法：将特异性无致病性级雌性Wistar大鼠分为4组：Sham + NS、Sham + MyoMed-205、MV + NS、MV + MyoMed-205。抑制剂组给予MyoMed-205，抑制TRIM63的表达。实验结束后，观察大鼠膈肌收缩力、线粒体结构和功能、氧化应激水平、自噬、细胞凋亡以及PPARα/PGC-1α通路的参与情况。结果：我们的研究结果表明，抑制TRIM63可预防机械通气（MV）引起的膈肌收缩功能障碍和萎缩。机制上，抑制TRIM63表达可显著上调PPARα和PGC-1α表达水平，改善线粒体动力学，增强线粒体膜电位，减少线粒体自噬和凋亡。在结构上，抑制TRIM63的表达改善了mv诱导的线粒体断裂、融合和裂变。结论：TRIM63在VIDD中的表达上调通过抑制PPARα/PGC-1α信号通路加重线粒体损伤，导致活性氧增加、线粒体自噬增加和细胞凋亡。抑制TRIM63的表达可增强线粒体功能，减少线粒体自噬和凋亡，减轻VIDD。因此，TRIM63可能作为预防和治疗VIDD的潜在靶点。

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引用次数: 0

The compound XueShuanTong promotes podocyte mitochondrial autophagy via the AMPK/mTOR pathway to alleviate diabetic nephropathy injury 复方血栓通通过AMPK/mTOR通路促进足细胞线粒体自噬，减轻糖尿病肾病损伤。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-03 DOI: 10.1016/j.mito.2025.102024

Chuangbiao Zhang , Weiwei Ren , Xiaohua Lu , Lie Feng , Jiaying Li , Beibei Zhu

The study aimed to elucidate the molecular mechanisms underlying the protective effects of Compound Xueshuantong (CXst) in the context of diabetic nephropathy (DN), a major cause of kidney failure driven by podocyte injury and metabolic dysfunction. Given the critical role of the AMPK/mTOR signaling pathway in regulating cellular energy balance, autophagy, and mitochondrial health, we focused on its involvement in podocyte function and how it might be influenced by CXst. Through a series of experiments, we found that CXst treatment led to the upregulation of key proteins involved in autophagy, such as LC3 and p62, as well as proteins critical for mitochondrial function, like PGC-1α. These molecular changes helped to counteract the damaging effects of high glucose levels on podocytes, which are central to maintaining the filtration function of the kidneys. Additionally, CXst’s ability to modulate the AMPK/mTOR pathway was shown to be a pivotal factor in its protective effects, as inhibition of AMPK significantly reduced these benefits. This comprehensive study provides strong evidence that CXst exerts its protective effects against DN by modulating the AMPK/mTOR pathway, thus preserving podocyte integrity and function. These findings suggest that CXst could be a promising candidate for the development of new therapeutic strategies for the treatment of DN, offering hope for better management of this challenging condition.

本研究旨在阐明复方血栓通（CXst）对糖尿病肾病（DN）保护作用的分子机制，糖尿病肾病是由足细胞损伤和代谢功能障碍引起的肾衰竭的主要原因。鉴于AMPK/mTOR信号通路在调节细胞能量平衡、自噬和线粒体健康方面的关键作用，我们关注其参与足细胞功能以及它如何受到CXst的影响。通过一系列实验，我们发现CXst处理导致参与自噬的关键蛋白上调，如LC3和p62，以及对线粒体功能至关重要的蛋白，如PGC-1α。这些分子变化有助于抵消高葡萄糖水平对足细胞的破坏性影响，足细胞是维持肾脏过滤功能的核心。此外，CXst调节AMPK/mTOR通路的能力被证明是其保护作用的关键因素，因为AMPK的抑制显著降低了这些益处。这项全面的研究提供了强有力的证据，证明CXst通过调节AMPK/mTOR通路发挥其对DN的保护作用，从而保持足细胞的完整性和功能。这些发现表明，CXst可能是开发新的DN治疗策略的有希望的候选者，为更好地管理这一具有挑战性的疾病提供了希望。

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引用次数: 0

Research progress on paternal mitochondrial inheritance: An overview 父系线粒体遗传研究进展综述。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-28 DOI: 10.1016/j.mito.2025.102019

Wen Hu , Jiting Zhang , Zhaoqi Wu , Yi Wu , Yuhui Hu , Xiaohui Hu , Jinguo Cao

Mitochondria are self-replicating organelles with their own DNA. They play a crucial role in biological, cellular and functional processes, such as energy production, metabolism, and signal transduction. Abnormal mitochondrial function can cause various diseases such as diabetes, tumour, Parkinson’s disease, hereditary optic neuropathy, and others. Although mitochondrial functions have been extensively and widely explored, studies on mitochondrial inheritance have been limited. Mitochondrial inheritance is traditionally thought to be maternal although small amounts of paternally transmitted mitochondria have been discovered on rare occasions, and the role of paternal mitochondria transmission to offspring has been largely ignored. This review highlights the present knowledge on mitochondrial inheritance, especially the controversy and the difficulties in investigating paternal mitochondrial inheritance. More significantly, we present a comprehensive description of the physiological functions of paternal mitochondria in children and discuss the animal model to explore the mechanism of paternal mitochondrial inheritance. This review may provide a theoretical and experimental basis for improving our understanding of paternal mitochondrial inheritance, and also provide new ideas for treating mitochondrial diseases.

线粒体是具有自身 DNA 的自我复制细胞器。它们在生物、细胞和功能过程（如能量生产、新陈代谢和信号转导）中发挥着至关重要的作用。线粒体功能异常可导致多种疾病，如糖尿病、肿瘤、帕金森病、遗传性视神经病变等。尽管线粒体功能已得到广泛深入的研究，但对线粒体遗传的研究却十分有限。线粒体遗传传统上被认为是母系遗传，尽管在极少数情况下发现了少量父系遗传的线粒体，但父系线粒体遗传给后代的作用在很大程度上被忽视了。本综述重点介绍了线粒体遗传方面的现有知识，尤其是在研究父系线粒体遗传方面存在的争议和困难。更重要的是，我们全面描述了父系线粒体在儿童中的生理功能，并讨论了探索父系线粒体遗传机制的动物模型。这篇综述可为提高我们对父系线粒体遗传的认识提供理论和实验依据，也可为治疗线粒体疾病提供新思路。

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引用次数: 0

Mitochondria in aging and age-associated diseases 线粒体在衰老和衰老相关疾病中的作用。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-27 DOI: 10.1016/j.mito.2025.102022

Sonu Pahal , Nirjal Mainali , Meenakshisundaram Balasubramaniam , Robert J. Shmookler Reis , Srinivas Ayyadevara

Mitochondria, essential for cellular energy, are crucial in neurodegenerative disorders (NDDs) and their age-related progression. This review highlights mitochondrial dynamics, mitovesicles, homeostasis, and organelle communication. We examine mitochondrial impacts from aging and NDDs, focusing on protein aggregation and dysfunction. Prospective therapeutic approaches include enhancing mitophagy, improving respiratory chain function, maintaining calcium and lipid balance, using microRNAs, and mitochondrial transfer to protect function. These strategies underscore the crucial role of mitochondrial health in neuronal survival and cognitive functions, offering new therapeutic opportunities.

线粒体是细胞能量的重要来源，在神经退行性疾病（NDDs）及其与年龄相关的进展中至关重要。本综述重点介绍线粒体动力学、有丝分裂、平衡和细胞器通讯。我们研究了衰老和 NDDs 对线粒体的影响，重点关注蛋白质聚集和功能障碍。前瞻性治疗方法包括加强有丝分裂、改善呼吸链功能、维持钙和脂质平衡、利用微RNA和线粒体转移来保护功能。这些策略强调了线粒体健康在神经元存活和认知功能中的关键作用，提供了新的治疗机会。

引用次数: 0

Transcription coupled repair occurrence in Trypanosoma cruzi mitochondria 克氏锥虫线粒体转录偶联修复的发生。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-22 DOI: 10.1016/j.mito.2025.102009

Bruno Marçal Repolês , Wesley Roger Rodrigues Ferreira , Antônio Vinicius de Assis , Isabela Cecília Mendes , Flávia Souza Morini , Camila Silva Gonçalves , Carolina Moura Costa Catta-Preta , Shana O. Kelley , Glória Regina Franco , Andrea Mara Macedo , Jeremy C. Mottram , Maria Cristina M. Motta , Stênio Perdigão Fragoso , Carlos Renato Machado

Although several proteins involved in DNA repair systems have been identified in the T. cruzi mitochondrion, limited information is available regarding the specific DNA repair mechanisms responsible for kinetoplast DNA (kDNA) maintenance. The kDNA, contained within a single mitochondrion, exhibits a highly complex replication mechanism compared to the mitochondrial DNA of other eukaryotes. The absence of additional mitochondria makes the proper maintenance of this single mitochondrion essential for parasite viability.

Trypanosomatids possess a distinct set of proteins dedicated to kDNA organization and metabolism, known as kinetoplast-associated proteins (KAPs). Despite studies identifying the localization of these proteins, their functions remain largely unclear. Here, we demonstrate that TcKAP7 is involved in the repair of kDNA lesions induced by UV radiation and cisplatin. TcKAP7 mutant cells exhibited phenotypes similar to those observed in Angomonas deanei following the deletion of this gene. This monoxenic trypanosomatid colonizes the gastrointestinal tract of insects and possesses a kinetoplast with a distinct shape and kDNA topology compared to T. cruzi, making it a suitable comparative model in this study. Additionally, we observed that DNA damage can trigger distinct signaling pathways leading to cell death. Furthermore, we elucidated the involvement of CSB in this response, suggesting a potential interaction between TcKAP7 and CSB proteins in transcription-coupled DNA repair. The results presented here describe, for the first time, the mechanism of mitochondrial DNA repair in trypanosomatids following exposure to UV radiation and cisplatin.

虽然在克氏T. crozi线粒体中已经发现了一些参与DNA修复系统的蛋白质，但有关着丝体DNA （kDNA）维持的特定DNA修复机制的信息有限。与其他真核生物的线粒体DNA相比，包含在单个线粒体内的kDNA表现出高度复杂的复制机制。额外线粒体的缺失使得这一线粒体的适当维持对寄生虫的生存至关重要。锥虫拥有一组独特的蛋白质，专门用于kDNA的组织和代谢，称为动质体相关蛋白（KAPs）。尽管研究确定了这些蛋白质的定位，但它们的功能在很大程度上仍不清楚。在这里，我们证明TcKAP7参与了紫外线辐射和顺铂诱导的kDNA损伤的修复。TcKAP7突变细胞表现出类似于该基因缺失后在deanei绒单胞菌中观察到的表型。这种单基因锥虫寄生在昆虫的胃肠道中，具有与克氏锥虫不同的形状和kDNA拓扑结构的着丝体，使其成为本研究的合适比较模型。此外，我们观察到DNA损伤可以触发导致细胞死亡的不同信号通路。此外，我们阐明了CSB在这一反应中的参与，表明TcKAP7和CSB蛋白在转录偶联DNA修复中可能存在相互作用。本文的研究结果首次描述了暴露于紫外线辐射和顺铂后锥虫线粒体DNA修复的机制。

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引用次数: 0

Large-scale screens identify a 19-Gene MitoScore for improved risk assessment in acute myeloid leukemia 大规模筛选鉴定19基因MitoScore以改善急性髓性白血病的风险评估

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-19 DOI: 10.1016/j.mito.2025.102011

Liting Niu , Hanfei Guo , Yijing Zhao

Background

AML exhibits substantial molecular and genetic heterogeneity. Therefore, identifying key biological processes and related genes involved in the pathogenesis, as well as contributing to therapeutic resistance, is imperative for enhancing clinical outcomes. However, the assessment of mitochondrial function in AML has gradually been acknowledged but has not been widely emphasized. Hence, prioritizing the identification of mitochondrial-related biomarkers is crucial to enhance existing stratification methodologies and guide decisions on risk-adapted therapies.

Methods

We systematically integrated and analyzed data from nine online AML transcriptomics sequencing databases, screening the Human.MitoCarta3.0 mitochondrial gene database to identify AML-specific mitochondrial genes. A prognostic mitochondrial score was developed using LASSO regression analysis in the HOVON database as training cohort (n = 618) and validated in another eight publicly available independent cohorts (n = 1,697).

Results

A 19-mitochondrial function gene AML score was further generated and exhibited high prognostic power in 2,315 AML patients, named as MitoScore. MitoScore was an independent survival prognosis biomarker (p < 0.001). The MitoScore effectively distinguishes several genetic abnormalities and significantly improves the ELN (European Leukemia Net) classification. Patients with a high MitoScore demonstrated a notably poor response to induction chemotherapy and related refractory AML (p < 0.001). In the favorable risk gene variant and cytogenetic abnormality group, MitoScore was significantly lower compared to patients without those variants. Conversely, in the adverse group, MitoScore was significantly higher compared to patients with favorable genetic abnormalities.

Conclusions

Our findings underscore the utility of the MitoScore as a powerful tool for refined risk stratification and predicting chemotherapy resistance.

daml表现出大量的分子和遗传异质性。因此，确定参与发病机制的关键生物学过程和相关基因，以及对治疗耐药的贡献，对于提高临床疗效至关重要。然而，对AML中线粒体功能的评估已逐渐得到承认，但尚未得到广泛重视。因此，优先鉴定线粒体相关的生物标志物对于增强现有的分层方法和指导风险适应疗法的决策至关重要。方法系统整合和分析9个在线AML转录组学测序数据库数据，筛选Human.MitoCarta3.0线粒体基因数据库，鉴定AML特异性线粒体基因。使用LASSO回归分析在HOVON数据库中建立预后线粒体评分作为训练队列（n = 618），并在另外8个公开的独立队列（n = 1,697）中进行验证。结果进一步生成了2315例AML患者的线粒体功能基因m19评分，并显示出较高的预后能力，命名为MitoScore。MitoScore是一种独立的生存预后生物标志物(p <；0.001)。MitoScore有效地区分了几种遗传异常，并显著改善了ELN（欧洲白血病网）分类。MitoScore高的患者对诱导化疗和相关难治性AML的反应明显较差(p <；0.001)。在有利风险基因变异和细胞遗传学异常组中，MitoScore明显低于无这些变异的患者。相反，在不良组中，MitoScore明显高于有利遗传异常患者。结论：我们的研究结果强调了MitoScore作为精细风险分层和预测化疗耐药的有力工具的实用性。

{"title":"Large-scale screens identify a 19-Gene MitoScore for improved risk assessment in acute myeloid leukemia","authors":"Liting Niu , Hanfei Guo , Yijing Zhao","doi":"10.1016/j.mito.2025.102011","DOIUrl":"10.1016/j.mito.2025.102011","url":null,"abstract":"<div><h3>Background</h3><div>AML exhibits substantial molecular and genetic heterogeneity. Therefore, identifying key biological processes and related genes involved in the pathogenesis, as well as contributing to therapeutic resistance, is imperative for enhancing clinical outcomes. However, the assessment of mitochondrial function in AML has gradually been acknowledged but has not been widely emphasized. Hence, prioritizing the identification of mitochondrial-related biomarkers is crucial to enhance existing stratification methodologies and guide decisions on risk-adapted therapies.</div></div><div><h3>Methods</h3><div>We systematically integrated and analyzed data from nine online AML transcriptomics sequencing databases, screening the Human.MitoCarta3.0 mitochondrial gene database to identify AML-specific mitochondrial genes. A prognostic mitochondrial score was developed using LASSO regression analysis in the HOVON database as training cohort (n = 618) and validated in another eight publicly available independent cohorts (n = 1,697).</div></div><div><h3>Results</h3><div>A 19-mitochondrial function gene AML score was further generated and exhibited high prognostic power in 2,315 AML patients, named as MitoScore. MitoScore was an independent survival prognosis biomarker (p < 0.001). The MitoScore effectively distinguishes several genetic abnormalities and significantly improves the ELN (European Leukemia Net) classification. Patients with a high MitoScore demonstrated a notably poor response to induction chemotherapy and related refractory AML (p < 0.001). In the favorable risk gene variant and cytogenetic abnormality group, MitoScore was significantly lower compared to patients without those variants. Conversely, in the adverse group, MitoScore was significantly higher compared to patients with favorable genetic abnormalities.</div></div><div><h3>Conclusions</h3><div>Our findings underscore the utility of the MitoScore as a powerful tool for refined risk stratification and predicting chemotherapy resistance.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"82 ","pages":"Article 102011"},"PeriodicalIF":3.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471230","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

Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions 耐力游泳加剧线粒体肌病小鼠高mtDNA缺失。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-14 DOI: 10.1016/j.mito.2025.102010

Sho Hanada , Kaori Ishikawa , Takanaga Shirai , Tohru Takemasa , Kazuto Nakada

Recent studies have reported that endurance exercise enhances mitochondrial function, facilitating discussions of its potential as a therapeutic strategy for mitochondrial diseases caused by the accumulation of mutant mitochondrial DNA (mtDNA). In this study, we assessed the effects of endurance exercise on muscle pathology in a mitochondrial disease mouse model (mito-miceΔ) that is characterized by severe clinical phenotypes owing to the predominant accumulation of mtDNA with a large-scale deletion (ΔmtDNA). Contrary to expectations that endurance exercise may enhance mitochondrial function, endurance exercise exacerbated muscle pathology in mito-miceΔ. Therefore, exercise interventions should be potentially avoided in patients with severe mitochondrial diseases.

最近的研究报道，耐力运动增强了线粒体功能，促进了其作为由突变线粒体DNA （mtDNA）积累引起的线粒体疾病的治疗策略的潜力的讨论。在这项研究中，我们在线粒体疾病小鼠模型（mito-miceΔ）中评估了耐力运动对肌肉病理的影响，该模型的特点是由于mtDNA的主要积累和大规模缺失（ΔmtDNA）导致严重的临床表型。与耐力运动可能增强线粒体功能的预期相反，耐力运动加剧了mito-miceΔ的肌肉病理。因此，严重线粒体疾病患者应尽量避免运动干预。

引用次数: 0

The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology 不寻常的怀疑：中间丝蛋白在线粒体形态中的新作用。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-02-03 DOI: 10.1016/j.mito.2025.102008

Irene M.G.M. Hemel , Carlijn Steen , Simon L.I.J. Denil , Gökhan Ertaylan , Martina Kutmon , Michiel Adriaens , Mike Gerards

Mitochondrial dynamics is crucial for cellular homeostasis. However, not all proteins involved are known. Using a protein–protein interaction (PPI) approach, we identified ITPRIPL2 for involvement in mitochondrial dynamics. ITPRIPL2 co-localizes with intermediate filament protein vimentin, supported by protein simulations. ITPRIPL2 knockdown reveals mitochondrial elongation, disrupts vimentin processing, intermediate filament formation, and alters vimentin-related pathways. Interestingly, vimentin knockdown also leads to mitochondrial elongation. These findings highlight ITPRIPL2 as vimentin-associated protein essential for intermediate filament structure and suggest a role for intermediate filaments in mitochondrial morphology. Our study demonstrates that PPI analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.

线粒体动力学对细胞稳态至关重要。然而，并不是所有的蛋白质都是已知的。利用蛋白相互作用（PPI）方法，我们确定了ITPRIPL2参与线粒体动力学。ITPRIPL2与中间丝蛋白vimentin共定位，得到了蛋白质模拟的支持。ITPRIPL2敲低揭示了线粒体伸长，破坏了波形蛋白加工，中间丝的形成，并改变了波形蛋白相关的途径。有趣的是，vimentin敲低也会导致线粒体伸长。这些发现强调了ITPRIPL2是中间丝结构所必需的vimentin相关蛋白，并提示中间丝在线粒体形态中的作用。我们的研究表明，PPI分析是鉴定新的线粒体动力学蛋白的有力方法。

引用次数: 0

Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings NDUFS7基因的新内含子变异导致线粒体复合体I组装缺陷，早期基底神经节和中脑受累，伴有进行性神经影像学表现。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-01-31 DOI: 10.1016/j.mito.2025.102007

Jaakko Oikarainen , Reetta Hinttala , Naemeh Nayebzadeh , Salla M. Kangas , Katariina Mankinen , Elisa Rahikkala , Hannaleena Kokkonen , Päivi Vieira , Maria Suo-Palosaari , Johanna Uusimaa

Leigh syndrome is the most common phenotype of mitochondrial disorders in children. This study demonstrates clinical, neuroradiological, and molecular genetic findings in siblings with Leigh syndrome and isolated complex I assembly defect associated with intronic c.16 + 5G > A variant in the NDUFS7 gene. Whole exome sequencing was carried out to identify the causative variant. The gene and protein expression of NDUFS7 were studied using patient-derived fibroblasts. Assembly of mitochondrial respiratory chain enzymes was analyzed using Blue Native PAGE. This study shows that the NDUFS7 c.16 + 5G > A variant (rs375282422) has a causative role in Leigh syndrome. Evolution of neuroimaging findings related to this gene variant are demonstrated.

Leigh综合征是儿童线粒体疾病中最常见的表型。本研究展示了Leigh综合征的兄弟姐妹的临床、神经放射学和分子遗传学发现，以及与NDUFS7基因的内含子c.16 + 5G > 变异相关的分离复合体I组装缺陷。全外显子组测序鉴定致病变异。利用患者源性成纤维细胞研究NDUFS7基因和蛋白的表达。使用Blue Native PAGE分析线粒体呼吸链酶的组装。本研究表明NDUFS7 c.16 + 5G > A变异（rs375282422）在Leigh综合征中具有致病作用。与该基因变异相关的神经影像学发现的进化被证明。

引用次数: 0

Sex-dependent adaptations in heart mitochondria from transgenic mice overexpressing cytochrome b5 reductase-3 过表达细胞色素b5还原酶-3的转基因小鼠心脏线粒体的性别依赖性适应。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-01-09 DOI: 10.1016/j.mito.2025.102004

Luz Marina Sánchez-Mendoza , José A. González-Reyes , Sandra Rodríguez-López , Miguel Calvo-Rubio , Pilar Calero-Rodríguez , Rafael de Cabo , M. Isabel Burón , José M. Villalba

Summary

Cytochrome b₅ reductase 3 (CYB5R3) overexpression upregulates mitochondrial biogenesis, function, and abundance in skeletal muscle and kidneys, and mimics some of the salutary effects of calorie restriction, with the most striking effects being observed in females. We aimed to investigate the mitochondrial adaptations prompted by CYB5R3 overexpression in the heart, an organ surprisingly overlooked in studies focused on this long-lived transgenic model despite the critical role played by CYB5R3 in supporting cardiomyocytes mitochondrial respiration. Given that CYB5R3 effects have been found to be sex-dependent, we focused our research on both males and females. CYB5R3 was efficiently overexpressed in cardiac tissue from transgenic mice, without any difference between sexes. The abundance of electron transport chain complexes markers and cytochrome c was higher in males than in females. CYB5R3 overexpression downregulated the levels of complexes markers in males but not females, without decreasing oxygen consumption capacity. CYB5R3 increased the size and abundance of cardiomyocytes mitochondria, and reduced thickness and preserved the length of mitochondria-endoplasmic reticulum contact sites in heart from males but not females. Metabolic changes were also highlighted in transgenic mice, with an upregulation of fatty acid oxidation markers, particularly in males. Our results support that CYB5R3 overexpression upregulates markers consistent with enhanced mitochondrial function in the heart, producing most of these actions in males, with illustrates the complexity of the CYB5R3-overexpressing transgenic model.

细胞色素b5还原酶3 （CYB5R3）过表达上调骨骼肌和肾脏的线粒体生物发生、功能和丰度，并模仿卡路里限制的一些有益效果，在女性中观察到最显著的效果。我们的目的是研究CYB5R3在心脏中的过表达引发的线粒体适应，尽管CYB5R3在支持心肌细胞线粒体呼吸中发挥着关键作用，但令人惊讶的是，在关注这种长寿转基因模型的研究中，CYB5R3却被忽视了。鉴于CYB5R3的影响是性别依赖的，我们将研究重点放在了男性和女性身上。CYB5R3在转基因小鼠心脏组织中高效过表达，无性别差异。电子传递链复合物、标记物和细胞色素c的丰度在雄性中高于雌性。CYB5R3过表达下调了雄性复合物标记物的水平，而雌性没有，但不降低氧气消耗能力。CYB5R3增加了雄性心肌细胞线粒体的大小和丰度，减少了线粒体-内质网接触点的厚度，保留了线粒体-内质网接触点的长度，而雌性心肌细胞没有。代谢变化在转基因小鼠中也很突出，脂肪酸氧化标记上调，尤其是在雄性小鼠中。我们的研究结果支持CYB5R3过表达上调与心脏线粒体功能增强一致的标记，在男性中产生大部分这些作用，并说明CYB5R3过表达转基因模型的复杂性。

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引用次数: 0