Mitochondrion最新文献_第7页

Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer’s disease DDQ在提高晚发型阿尔茨海默病线粒体健康和认知功能方面的治疗潜力

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-28 DOI: 10.1016/j.mito.2025.102036

Sudhir Kshirsagar , Rainier Vladlen Alvir , Jangampalli Adi Pradeepkiran , Arubala P. Reddy , P. Hemachandra Reddy

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

阿尔茨海默病（AD）是一种以认知能力下降、线粒体功能障碍和神经炎症为特征的神经退行性疾病。这项研究评估了DDQ的治疗潜力，DDQ是一种小分子，在人源化Abeta敲入蛋白（hAbKI）小鼠中代表晚发性AD。我们的研究结果表明，与未治疗的hAbKI小鼠相比，DDQ治疗显著改善了认知表现，通过行为测试评估，包括旋转道路、开阔场地、y迷宫和莫里斯水迷宫。在分子水平上，DDQ促进了线粒体的生物发生，如PGC1α、NRF1和TFAM等关键蛋白的表达增强。此外，DDQ治疗促进了线粒体自噬，如PINK1和Parkin水平升高所示，并减少了神经炎症，如Iba1和GFAP水平下降所反映。透射电镜分析显示，ddq处理小鼠线粒体形态明显改善，线粒体长度增加，线粒体数量减少。此外，DDQ治疗导致有丝分裂空泡增加，表明它有效地去除功能失调的线粒体。综上所述，我们的研究结果首次支持DDQ作为迟发性AD的有希望的神经保护剂的潜力，解决线粒体功能障碍，神经炎症和认知能力下降。我们的研究重点是开发调节线粒体自噬、线粒体动力学和衰老、AD和其他神经退行性疾病的神经炎症途径的小分子。

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引用次数: 0

Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue PGC-1α的缺失导致白色脂肪组织线粒体能力、ROS处理和代谢应激适应性反应的特异性改变

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-27 DOI: 10.1016/j.mito.2025.102034

Anders Gudiksen, Eva Zhou, Louise Pedersen, Catherine A. Zaia, Cecilie E. Wille, Elisabeth V. Eliesen, Henriette Pilegaard

White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mitochondria are important sources of reactive oxygen species (ROS) and oxidative damage may potentially derail adipocyte function when mitochondrial homeostasis is challenged by overproduction of ROS. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α is a transcriptional co-activator that in skeletal muscle plays a central role in mitochondrial biogenesis and function but whether PGC-1α is equally important for mitochondrial function and adaptations in white adipose tissue remains to be fully resolved. The aim of the present study was to characterize the necessity of adipocyte PGC-1α for adaptive regulation of mitochondrial function in distinct white adipose depots. PGC-1α adipose tissue-specific knockout (ATKO) and floxed littermate control mice (CTRL) were subjected to either 24 h of fasting or 48 h of cold exposure. Bioenergetics, ROS handling, basal and adaptive protein responses, markers of protein damage as well as lipid cycling capacity and regulation were characterized in distinct WAT depots.

ATKO mice demonstrated impairments in respiration as well as reduced OXPHOS protein content in fed and fasted conditions. Increased ROS emission in tandem with diminished mitochondrial antioxidant defense capacity resulted in increased protein oxidation in ATKO WAT. Adipose tissue PGC-1α knockout also led to changes in regulation of lipolysis and potentially triglyceride reesterification in WAT. In conclusion, PGC-1α regulates adipose tissue mitochondrial respiration and ROS balance as well as lipid cycling during metabolic challenges in a depot specific manner.

白色脂肪组织（WAT）通过控制脂肪分解和再酯化调节途径，在线粒体生物能量支持的促进下，为全身能量消耗提供脂质燃料代谢支持。线粒体是活性氧（ROS）的重要来源，当线粒体内稳态受到活性氧过量产生的挑战时，氧化损伤可能会破坏脂肪细胞的功能。过氧化物酶体增殖体激活受体- γ共激活因子(PGC)-1α是一种转录共激活因子，在骨骼肌中对线粒体的生物发生和功能起着核心作用，但PGC-1α是否对白色脂肪组织的线粒体功能和适应性同样重要仍有待完全解决。本研究的目的是表征脂肪细胞PGC-1α对不同白色脂肪库线粒体功能适应性调节的必要性。PGC-1α脂肪组织特异性敲除小鼠（ATKO）和固定窝偶对照小鼠（CTRL）进行24小时禁食或48小时冷暴露。研究了不同WAT库的生物能量学、活性氧处理、基础和适应性蛋白质反应、蛋白质损伤标志物以及脂质循环能力和调节。在喂食和禁食条件下，ATKO小鼠表现出呼吸损伤以及OXPHOS蛋白含量降低。随着线粒体抗氧化防御能力的减弱，ROS释放增加导致ATKO WAT中蛋白质氧化增加。脂肪组织PGC-1α敲除也导致WAT中脂肪分解和甘油三酯再酯化调节的变化。综上所述，PGC-1α以一种特定的方式调节脂肪组织线粒体呼吸和ROS平衡以及代谢挑战过程中的脂质循环。

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引用次数: 0

Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer’s disease 自噬增强剂对阿尔茨海默病中β -淀粉样蛋白诱导的线粒体和突触毒性的有益作用

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-27 DOI: 10.1016/j.mito.2025.102038

Sudhir Kshirsagar , Arubala P. Reddy , P.Hemachandra Reddy

The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer’s disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers—Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)—using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.

我们的研究目的是探讨线粒体自噬增强剂对突变淀粉样前体蛋白（APP）和β淀粉样蛋白（Aβ）诱导的阿尔茨海默病（AD）线粒体和突触毒性的有益作用。二十年来的研究强调了线粒体功能障碍和突触损伤在早发性和晚发性AD发病机制中的关键作用。新出现的证据表明，受损线粒体的清除受损是AD的早期病理事件，将线粒体自噬增强剂定位为潜在的治疗候选者。本研究利用永生化小鼠海马（HT22）神经元，确定了四种线粒体自噬增强剂尿素A （UA）、肌动蛋白、番茄碱和烟酰胺核苷（NR）的最佳剂量。用突变体APP (mAPP) cDNA转染HT22细胞，并用增强子处理。通过评估参与线粒体动力学、生物发生、线粒体自噬和突触功能以及细胞存活和线粒体呼吸的基因的mRNA和蛋白表达水平来评估其效果。同时检测处理和未处理的mAPP-HT22细胞的线粒体形态。结果显示，mAPP-HT22细胞表现出线粒体分裂增加，融合减少，突触和线粒体自噬相关基因下调，细胞存活减少，线粒体呼吸受损，线粒体过度碎片化和缩短。用线粒体自噬增强剂治疗逆转了这些缺陷，恢复了线粒体和突触的健康。观察到细胞存活率提高，线粒体融合、突触和线粒体自噬基因上调，线粒体结构改善，碎片化减少。值得注意的是，UA显示了最强大的缓解效果。这些发现强调了线粒体自噬增强剂的治疗潜力，特别是UA，作为治疗阿尔茨海默病线粒体和突触功能障碍的有希望的候选者。

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引用次数: 0

Mitochondrial DNA copy number and Alzheimer’s disease and Parkinson disease 线粒体DNA拷贝数与阿尔茨海默病和帕金森病的关系

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2025-03-27 DOI: 10.1016/j.mito.2025.102032

Pei Qin , Xiaojuan Chen , Panpan Ma , Xinying Li , Yunying Lin , Xiaoning Liu , Xiaoyan Liang , Tianhang Qin , Junyan Liang , Jipeng Ouyang

Introduction

A systematic review on the association of mitochondrial DNA copy number (mtDNA-CN) with Alzheimer’s disease (AD) and Parkinson disease (PD) is lacking and the causal relationship remains unclear.

Objective

We aimed to conduct a systematic review of observational studies on the association of mtDNA-CN with AD and PD and perform a bidirectional 2-sample Mendelian randomization (MR) study to investigate their causal relationships.

Methods

PubMed, Embase, and Web of Science were searched for eligible studies before Jan 2025. The causal links were conducted with inverse-variance weighted (IVW) method as the main analysis.

Results

Fourteen case-control and 2 cohort studies investigated the association between mtDNA-CN and AD, with 13 reporting decreased mtDNA-CN associated with increased risk of AD and 3 showing no significant association. All the studies (9 case-control, 1 cross-sectional, 2 cohort studies) observed the relation between mtDNA-CN and PD except for 3 studies reporting no significant association. In MR analysis, genetically predicted mtDNA-CN was not associated with AD and PD, whereas genetically predicted AD (β −0.085, 95 % CI −0.156 to −0.013; P = 0.02) but not PD was associated with mtDNA-CN. Sensitivity and replication analyses showed a stable finding.

Discussion

The systematic review found limited observational studies on mtDNA-CN and AD and PD and majority were case-control study. Findings of the bidirectional MR study did not support a causal effect of mtDNA-CN in the development of AD and PD but found that AD can lead to decreased levels of mtDNA-CN, which suggest mtDNA-CN as a potential biomarker of AD.

关于线粒体DNA拷贝数（mtDNA-CN）与阿尔茨海默病（AD）和帕金森病（PD）相关性的系统综述缺乏，其因果关系尚不清楚。目的：我们旨在对mtDNA-CN与AD和PD相关性的观察性研究进行系统回顾，并进行双向双样本孟德尔随机化（MR）研究，以探讨它们之间的因果关系。方法检索spubmed、Embase和Web of Science，检索2025年1月前符合条件的研究。以反方差加权法（IVW）为主要分析方法进行因果关系分析。结果14项病例对照研究和2项队列研究调查了mtDNA-CN与AD之间的关系，其中13项报告mtDNA-CN降低与AD风险增加相关，3项报告无显著相关性。所有研究（9个病例对照，1个横断面研究，2个队列研究）均观察到mtDNA-CN与PD之间的关系，除了3个研究报告无显著相关性。在MR分析中，遗传预测的mtDNA-CN与AD和PD无关，而遗传预测的AD (β - 0.085, 95% CI - 0.156 ~ - 0.013；P = 0.02)，但PD与mtDNA-CN无关。敏感性和重复性分析显示了稳定的结果。系统评价发现mtDNA-CN与AD和PD的观察性研究有限，且大多数为病例对照研究。双向MR研究结果不支持mtDNA-CN在AD和PD发展中的因果关系，但发现AD可导致mtDNA-CN水平下降，这表明mtDNA-CN可能是AD的潜在生物标志物。

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引用次数: 0

Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling Drp1基因敲低会加重肥胖引起的心功能障碍和重构。

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.

肥胖是保留射血分数（HFpEF）心力衰竭的独立危险因素。动力蛋白相关蛋白1 （Drp1）是线粒体形态、生物能量学和质量控制的关键调节因子。内源性Drp1在肥胖诱导的HFpEF中的作用在很大程度上仍然未知。本研究将成年杂合Drp1基因敲除（Drp1fl/+）小鼠与αMHC-MerCreMer小鼠杂交，并注射他莫昔芬在心脏诱导Drp1基因异质敲除（hetCKO）。对照组和hetCKO小鼠在高脂肪饮食（HFD）喂养18周后表现出相似的体重和血糖增加，并出现胰岛素抵抗。HFD对心脏收缩力没有影响，但在对照组和hetCKO小鼠心脏中引起舒张功能障碍、纤维化、细胞死亡和炎症。重要的是，所有这些不良反应在hetCKO小鼠的心脏中都加剧了，表明心脏重塑和舒张功能障碍加重。HFD诱导的线粒体裂变被阻断，而能量缺乏在tcko心脏中被夸大。这些影响与线粒体自噬抑制线粒体质量控制、细胞凋亡和氧化应激增加有关。这些发现表明，内源性Drp1可能通过调节线粒体自噬、氧化应激、线粒体功能、细胞凋亡和炎症，在限制代谢应激诱导的心功能障碍中发挥重要作用。我们的研究为内源性Drp1如何在代谢应激诱导的HFpEF中发挥有益作用提供了重要的见解。

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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 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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