Mitochondrial Communications最新文献

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Mitochondrial Communications

Pub Date : 2025-01-01

引用次数: 0

Exploring the oncogenic impact of heteroplasmic de novo MT-ND5 truncating mutations 探索异质新生MT-ND5截断突变对肿瘤的影响

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.03.001

Yuanyuan Wu , Jiangbin Ye , Zhenglong Gu

Numerous mitochondrial DNA (mtDNA) variants are associated with cancers, yet the causal link remains inconclusive. Using DddA-derived cytosine base editors, we induced de novo truncating mutations in MT-ND5 in HEK293 cells, establishing heteroplasmy, the coexistence of mutant and wild-type mtDNA. This study aimed to investigate the full molecular etiology following these deleterious mtDNA mutations, particularly in oncogenesis. We found that low to moderate heteroplasmic levels of the mutants were sufficient to impair mitochondrial functions and alter cellular redox status. Cellular adaptation to elevated ROS (Reactive Oxygen Species), energy crisis, and altered redox status was observed across varying heteroplasmy levels. Increased oncogenic potential was confirmed through in vitro oncogenesis and in vivo xenograft assays. Transcriptomic analysis revealed upregulated migration, invasion, and genome instability pathways, and downregulated ROS scavenging pathways. Our results demonstrate that MT-ND5 mutations drive cancer progression by increasing cellular ROS and genome instability, and by altering the redox balance and epigenetic landscapes.

许多线粒体 DNA（mtDNA）变异与癌症有关，但其中的因果关系仍未确定。利用 DddA 衍生的胞嘧啶碱基编辑器，我们在 HEK293 细胞中诱导了 MT-ND5 的新截断突变，建立了异质体，即突变型和野生型 mtDNA 的共存。本研究旨在探究这些有害 mtDNA 突变后的全部分子病因，尤其是在肿瘤发生过程中。我们发现，低到中等程度的异质突变体足以损害线粒体功能并改变细胞氧化还原状态。在不同的异质体水平下，都能观察到细胞对 ROS（活性氧）升高、能量危机和氧化还原状态改变的适应性。体外肿瘤发生和体内异种移植试验证实了致癌潜力的增加。转录组分析表明，迁移、侵袭和基因组不稳定性通路上调，ROS 清除通路下调。我们的研究结果表明，MT-ND5 突变通过增加细胞 ROS 和基因组不稳定性，以及通过改变氧化还原平衡和表观遗传景观来推动癌症进展。

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引用次数: 0

Mitochondrial heterogeneity: within and between cells 线粒体异质性：细胞内和细胞间

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.03.002

Shiyuan Chen , Jiangbin Ye , Zhenglong Gu

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Mitochondrial Communications

Pub Date : 2025-01-01

引用次数: 0

Are patients with mitochondrial diseases prone to inflammatory and immune dysfunction: A scoping review and retrospective chart analysis 线粒体疾病患者是否容易发生炎症和免疫功能障碍：范围回顾和回顾性图表分析

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.03.003

Eiti Rautela , Savannah Sauve , Nikki Kovac , Edana Cassol , David Dyment , Martin Holcik

Mitochondrial diseases (MDs) are a significant patient burden and are linked to the dysregulation of various metabolic processes and cellular energy production. Additionally, mitochondria play a central role in regulating immune function and inflammatory response. This study aimed to examine the connection between MD and immune dysfunction, including inflammation as a specific immune response to infection. A scoping literature review and retrospective chart review were conducted. The scoping review followed the five-stage methodology framework by Arksey and O'Malley, extracting 1823 articles from PubMed using Covidence as managing software, with full texts of 10 articles analyzed. A retrospective patient chart review was conducted on 92 patients with a confirmed diagnosis of MD from the Children's Hospital of Eastern Ontario. The scoping review identified cases of MDs associated with inflammation, including individuals with POLG-associated disease. Immune dysfunction was observed in a subset of complex MDs, particularly in individuals with biallelic variation in POLGF and ATAD3A, who had a heavy burden of disease. The results from both the scoping and retrospective chart reviews suggest an association between complex MD and altered inflammatory and immune functions.

线粒体疾病（MDs）是一个重要的患者负担，与各种代谢过程和细胞能量产生的失调有关。此外，线粒体在调节免疫功能和炎症反应中发挥核心作用。本研究旨在探讨MD与免疫功能障碍之间的联系，包括炎症作为对感染的特异性免疫反应。进行了范围文献回顾和回顾性图表回顾。范围审查遵循Arksey和O'Malley的五阶段方法框架，使用Covidence作为管理软件从PubMed中提取1823篇文章，并分析了10篇文章的全文。回顾性分析了东安大略儿童医院确诊为MD的92例患者。范围审查确定了与炎症相关的MDs病例，包括患有polg相关疾病的个体。在复杂MDs的一个亚群中观察到免疫功能障碍，特别是在POLGF和ATAD3A双等位基因变异的个体中，他们有沉重的疾病负担。范围研究和回顾性图表回顾的结果表明，复杂MD与炎症和免疫功能改变之间存在关联。

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引用次数: 0

Nucleotide imbalance fuels ageing-associated inflammation 核苷酸失衡会引发与衰老相关的炎症

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.11.002

Tao Long, Da Jia, Lin Zhao

引用次数: 0

Off-target effects of mitochondrial oxidative phosphorylation inhibitors are common and can compromise the viability of cultured cells 线粒体氧化磷酸化抑制剂的脱靶效应是常见的，可以损害培养细胞的活力

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.12.001

Natalya Kozhukhar, Mikhail F. Alexeyev

Mitochondrial respiratory chain inhibitors (MRCIs) are indispensable for studying cellular bioenergetics and its effects on various cellular processes. However, their off-target (those not mediated by respiratory chain inhibition) effects remain incompletely understood, even though their comprehension is crucial for the accurate interpretation of experimental outcomes. Here, we use four isogenic cell line pairs, which either have mitochondrial DNA (mtDNA) or lack it (ρ⁺ or ρ⁰ cells, respectively), to assess the possible off-target effects of widely used MRCIs antimycin A, oligomycin A, rotenone, and carbonyl cyanide m-chlorophenylhydrazone (CCCP). We examined clonogenic growth of ρ⁰ cells and ρ⁺ cells under conditions that either require the functional respiratory chain or do not. Unexpectedly, ρ⁰ cells were sensitive to rotenone and antimycin A, even though these cells lack functional complex I and complex III, respectively, suggesting a nonspecific effect of these drugs. Furthermore, ρ⁰ cells were more sensitive to CCCP than their ρ⁺ counterparts. Intriguingly, the loss of the clonogenic potential in ρ⁺ 143B cells could not be precisely correlated to the decrement of the mitochondrial inner membrane potential. These findings underscore the significance of off-target effects of MRCIs, which must be carefully considered when designing, conducting, and interpreting experiments involving these inhibitors.

线粒体呼吸链抑制剂（MRCIs）是研究细胞生物能量学及其对各种细胞过程的影响所不可缺少的。然而，尽管对它们的理解对于准确解释实验结果至关重要，但它们的脱靶效应（不通过呼吸链抑制介导的）仍未完全了解。在这里，我们使用四个等基因细胞系对，要么有线粒体DNA (mtDNA)，要么缺乏线粒体DNA（分别为ρ+或ρ0细胞），来评估广泛使用的MRCIs抗霉素A、寡霉素A、鱼tenone和羰基氰化间氯苯腙（CCCP）可能的脱靶效应。我们检查了在需要或不需要功能性呼吸链的条件下，ρ0细胞和ρ+细胞的克隆生长。出乎意料的是，ρ0细胞对鱼藤酮和抗霉素A敏感，尽管这些细胞分别缺乏功能性复合物I和复合物III，这表明这些药物具有非特异性作用。此外，ρ0细胞比ρ+细胞对CCCP更敏感。有趣的是，在ρ+ 143B细胞中克隆生成电位的丧失不能精确地与线粒体内膜电位的衰减相关。这些发现强调了MRCIs脱靶效应的重要性，在设计、实施和解释涉及这些抑制剂的实验时必须仔细考虑这一点。

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Mitochondrial Communications

Pub Date : 2025-01-01

引用次数: 0

Frontiers in LONP1 research: Unraveling molecular mechanisms, disease associations, and therapeutic strategies LONP1研究前沿：揭示分子机制、疾病关联和治疗策略

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.10.001

Wenwen Xi , Zhiyan Zhang , Yi Su , Shuyi Wang , Yangzheng Ou , Bin Lu

LONP1 is a conserved mitochondrial AAA + protease central to mitochondrial proteostasis. This review summarizes its structural features, protease-chaperone functions, and roles in metabolic regulation (heme/sulfur/steroid pathways) and disease. In cancer, LONP1 overexpression drives tumor progression via metabolic reprogramming, EMT induction, metastasis, and therapy resistance, establishing it as a pan-cancer therapeutic target. Inhibitors face delivery and selectivity challenges, prompting future strategies like mitochondrial-targeted delivery and allosteric modulators. Research directions include mechanistic studies and clinical translation for cancer and neurodegenerative disorders.

LONP1是一种保守的线粒体AAA +蛋白酶，对线粒体蛋白质平衡至关重要。本文综述了其结构特征、蛋白酶伴侣的功能及其在代谢调节（血红素/硫/类固醇途径）和疾病中的作用。在癌症中，LONP1过表达通过代谢重编程、EMT诱导、转移和治疗耐药驱动肿瘤进展，使其成为泛癌症治疗靶点。抑制剂面临递送和选择性的挑战，促使未来的策略如线粒体靶向递送和变构调节剂。研究方向包括肿瘤和神经退行性疾病的机制研究和临床转化。

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Mitochondrial Communications

Pub Date : 2025-01-01

引用次数: 0

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