Mitochondrion最新文献

英文中文

Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-04 DOI: 10.1016/j.mito.2025.102023

Dan Wu , Qingxun Hu , Huimin Li , Yun Yin , Pei Wang , Wang Wang

Obesity is an independent risk factor for heart failure with preserved ejection fraction (HFpEF). Dynamin related protein 1 (Drp1) is a key regulator of mitochondrial morphology, bioenergetics and quality control. The role of endogenous Drp1 in obesity induced HFpEF remains largely unknown. Here, adult heterozygous Drp1 floxed (Drp1^fl/+) mice were bred with αMHC-MerCreMer mice and injected with tamoxifen to induce heterogenous Drp1 knockout (hetCKO) in the heart. Control and hetCKO mice exhibited similar increases in body weight and blood glucose and developed insulin resistance after 18-week high-fat diet (HFD)-fed. HFD had no effect on cardiac contractility but induced diastolic dysfunction, fibrosis, cell death and inflammation in Control and hetCKO mice hearts. Importantly, all these adverse effects were exacerbated in the hearts of hetCKO mice, suggesting aggravated cardiac remodeling and diastolic dysfunction. HFD induced mitochondrial fission was blocked, whereas energy deficiency was exaggerated in hetCKO hearts. These effects were associated with suppressed mitochondrial quality control via mitophagy, and increased apoptosis and oxidative stress. These findings suggest that endogenous Drp1 may play an important role in limiting metabolic stress induced heart dysfunction through regulating mitophagy, oxidative stress, mitochondrial function, apoptosis, and inflammation. Our study provides critical insights into how endogenous Drp1 plays a beneficial role in metabolic stress-induced HFpEF.

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引用次数: 0

Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway

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.

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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

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.

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引用次数: 0

Research progress on paternal mitochondrial inheritance: An overview

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

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

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.

{"title":"Transcription coupled repair occurrence in Trypanosoma cruzi mitochondria","authors":"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","doi":"10.1016/j.mito.2025.102009","DOIUrl":"10.1016/j.mito.2025.102009","url":null,"abstract":"<div><div>Although several proteins involved in DNA repair systems have been identified in the <em>T. cruzi</em> 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.</div><div>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 <em>Angomonas deanei</em> 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 <em>T. cruzi</em>, 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.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"83 ","pages":"Article 102009"},"PeriodicalIF":3.9,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492763","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

Large-scale screens identify a 19-Gene MitoScore for improved risk assessment in acute myeloid leukemia

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.

{"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

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.

引用次数: 0

The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology

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.

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

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.

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全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

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