Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Suite 104, Baltimore, MD, 21201, USA.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
Cell Mol Life Sci. 2022 Oct 29;79(11):574. doi: 10.1007/s00018-022-04604-8.
Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized.
线粒体通过在能量生成和几个重要途径（包括细胞凋亡和炎症）中的调节作用，对真核生物的生命至关重要。线粒体功能障碍是许多病理学发病机制的主要问题，包括神经退行性疾病，如帕金森病（PD）、阿尔茨海默病（AD）、亨廷顿病（HD）和肌萎缩侧索硬化症（ALS）、糖尿病、心血管疾病等。蛋白质毒性应激，这里定义为线粒体中异常蛋白质积累导致的生物能量活性降低，可能与与疾病相关的线粒体和细胞衰退有关。各种质量控制途径，如线粒体未折叠蛋白反应（mtUPR）、异常线粒体蛋白的泛素（Ub）依赖性降解和线粒体特异性自噬（mitophagy），对蛋白质毒性应激做出反应并消除有缺陷的蛋白质或功能失调的线粒体。本文简要综述了与疾病相关的异常蛋白质如何影响线粒体功能的机制，以及对抗线粒体蛋白质毒性的线粒体质量控制途径的概述。我们重点介绍依赖 Ub 介导的蛋白质降解的线粒体质量控制机制，如线粒体特异性自噬和 Ub 蛋白酶体系统（UPS）的线粒体臂。我们强调了从更广泛的角度理解这些途径如何保护线粒体免受蛋白质毒性应激的重要性，以更好地理解重叠病理生理途径中的线粒体蛋白质毒性。这些机制在疾病发展中的意义也简要总结。
