Mitochondrial Communications最新文献

英文中文

Decoding the influence of mitochondrial Ca2+ regulation on neurodegenerative disease progression 解码线粒体Ca2+调节对神经退行性疾病进展的影响

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.01.001

Jianxu Sun , Ge Gao , Sitong Wang , Hongmei Liu , Tie-Shan Tang

Mitochondria are pivotal hubs in maintaining cellular homeostasis, encompassing vital processes such as bioenergetics, redox regulation, Ca²⁺ signaling, and programmed cell death. Ca²⁺ is a key second messenger within cells, paramount in numerous critical biological processes. The maintenance of mitochondrial calcium homeostasis relies on a delicate balance between Ca²⁺ uptake and efflux. At the mitochondrial level, Ca²⁺ serves a dual function, participating in essential physiological processes such as ATP production and the regulation of mitochondrial metabolisms and contributing to pathophysiological events, including cell death and cancer metastasis. Alterations in mitochondrial Ca²⁺ (Ca²⁺_mito) levels influence cellular activity and functionality. The regulation of mitochondrial Ca²⁺ homeostasis involves the collaborative participation of the mitochondrial Ca²⁺ transporter and the mitochondria-endoplasmic reticulum contact sites (MERCS). This review provides a comprehensive overview of current knowledge regarding the regulation of mitochondrial Ca²⁺ homeostasis and its implications in both physiological processes and neurodegenerative disorders. Moreover, we highlight potential opportunities and challenges in developing therapeutic interventions that target mitochondrial Ca²⁺ homeostasis and its regulators, such as novel drug delivery systems and specific calcium-modulating agents.

线粒体是维持细胞稳态的关键枢纽，包括生物能量学、氧化还原调节、Ca2+信号传导和程序性细胞死亡等重要过程。Ca2+是细胞内的关键第二信使，在许多关键的生物过程中至关重要。线粒体钙稳态的维持依赖于Ca2+摄取和外排之间的微妙平衡。在线粒体水平，Ca2+具有双重功能，参与必要的生理过程，如ATP的产生和线粒体代谢的调节，并有助于病理生理事件，包括细胞死亡和癌症转移。线粒体Ca2+ (Ca2+mito)水平的改变影响细胞活性和功能。线粒体Ca2+稳态的调节涉及线粒体Ca2+转运体和线粒体-内质网接触位点（MERCS）的协同参与。这篇综述提供了关于线粒体Ca2+稳态调节及其在生理过程和神经退行性疾病中的意义的当前知识的全面概述。此外，我们强调了开发针对线粒体Ca2+稳态及其调节因子的治疗干预措施的潜在机遇和挑战，例如新型药物输送系统和特定的钙调节剂。

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引用次数: 0

Mitochondrial dynamic changes and energy surplus 线粒体动态变化与能量过剩

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.11.001

Kaiyue Wu, Shuang Shen

Mitochondrial homeostasis is essential for cell survival and metabolic balance. This review systematically examines the molecular mechanisms, pathological correlations, and regulatory relationships among three major processes: mitochondrial homeostasis, lipoacylation modification, and mitochondrial overheating (excess energy). Mitochondrial dynamic balance adapts to energy demands through division mediated by Drp1, as well as regulation by Mfn1/2 and OPA1 for fusion. Lipoacylation activates PDH and α-KGDHC, which ensures metabolic efficiency and reduces ROS. Overheating characterized by increased ATP/ADP ratios, an enhanced ETC reducing state, and ROS accumulation, disrupts the first two processes and creates a vicious cycle. This network disorder is a common pathological basis for neurodegenerative diseases (such as CMT2A, AD), cardiovascular diseases (such as dilated cardiomyopathy), and metabolic diseases (such as type 2 diabetes and NAFLD). However, the details of these sensing pathways regulation remain unclear and require further investigation. This review aims to provide a theoretical framework for researching and treating diseases related to mitochondrial dysfunction.

线粒体稳态对细胞存活和代谢平衡至关重要。本文系统地探讨了线粒体稳态、脂酰化修饰和线粒体过热（能量过剩）这三个主要过程之间的分子机制、病理相关性和调节关系。线粒体动态平衡通过Drp1介导的分裂以及Mfn1/2和OPA1对融合的调节来适应能量需求。脂酰化激活PDH和α-KGDHC，保证代谢效率，减少ROS。过热以ATP/ADP比值增加、ETC还原状态增强和ROS积累为特征，破坏了前两个过程，形成了恶性循环。这种网络障碍是神经退行性疾病（如CMT2A、AD）、心血管疾病（如扩张型心肌病）、代谢性疾病（如2型糖尿病、NAFLD）的共同病理基础。然而，这些传感通路调控的细节仍不清楚，需要进一步研究。本文旨在为线粒体功能障碍相关疾病的研究和治疗提供理论框架。

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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

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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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。

引用次数: 0

Powering forward: A year of discovery in mitochondrial science 前进：线粒体科学发现的一年

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.12.003

Du Feng, Quan Chen

引用次数: 0

Mitochondrial Communications

Pub Date : 2025-01-01 DOI: 10.1016/j.mitoco.2025.08.001

Valeria Lobanova , Ivan Kozenkov , Eldar Khaibulin , Maria Tatarkina , Bogdan Efimenko , Viktoria Skripskaya , Akhsarbek H. Dzhigkaev , Anastasia S. Krylova , Anastasia V. Prokopenko , Stepan V. Toshchakov , Andrey Goncharov , Konstantin Popadin , Konstantin V. Gunbin

The origin and expansion of mitochondrial somatic variants, influenced by tissue-specific mutagenesis and selection, are not well understood despite their relevance to aging and age-related diseases. Postmitotic tissues, such as skeletal muscles, are particularly underexplored, even though mtDNA variant evolution in these tissues can differ significantly from that in proliferative tissues. To address this, we analyzed mitochondrial heteroplasmy in skeletal muscle samples from an osteoarthritic cohort (N = 105). We observed that the age-related dynamics of two famous variants m.189A > G and m.408T > A in our cohort is indistinguishable from their dynamics in random control cohort, suggesting that they are not a cause of muscular problems, but rather mark the age-related processes in muscles. We also observed that when adjusted by age and gender, carriers of these variants tend to have higher BMI, body weight, and muscle strength than non-carriers. Putting together all the lines of evidence, we propose that these variants are able to rapidly expand through selfish dynamics, which is especially pronounced in hypertrophic muscle fibers of individuals with higher body weight. Further investigation is necessary to clarify this hypothesis.

受组织特异性突变和选择影响的线粒体体细胞变异的起源和扩展，尽管它们与衰老和与年龄相关的疾病有关，但尚未得到很好的理解。有丝分裂后组织，如骨骼肌，尤其没有得到充分的研究，尽管这些组织中的mtDNA变异进化可能与增殖组织中的mtDNA变异进化有很大不同。为了解决这个问题，我们分析了来自骨关节炎队列（N = 105）的骨骼肌样本的线粒体异质性。我们观察到，在我们的队列中，两个著名的m.189A >； G和m.408T >； A的年龄相关动态与随机对照队列中的动态无法区分，这表明它们不是肌肉问题的原因，而是肌肉中与年龄相关的过程的标志。我们还观察到，当根据年龄和性别进行调整时，这些变异的携带者往往比非携带者具有更高的BMI、体重和肌肉力量。综合所有的证据，我们提出这些变异能够通过自私的动力迅速扩展，这在体重较高的个体的肥厚肌纤维中尤为明显。需要进一步的调查来澄清这一假设。

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