Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
Ann N Y Acad Sci. 2010 Jul;1201:147-56. doi: 10.1111/j.1749-6632.2010.05631.x.
Pathogenic mutation in mtDNA and mitochondrial dysfunction are associated with mitochondrial diseases. In this review, we discuss the oxidative stress-elicited mitochondrial protein modifications that may contribute to the pathophysiology of mitochondrial diseases. We demonstrated that excess ROS produced by defective mitochondria could increase the acetylation of microtubule proteins through the suppression of Sirt2, which results in perinuclear distribution of mitochondria in skin fibroblasts of patients with CPEO syndrome. Our recent work showed that mitochondrial dysfunction-induced oxidative stress can disrupt protein degradation system by inhibiting the ubiquitin-proteasome pathway and protease activity in human cells harboring mutant mtDNA. This in turn causes accumulation of aberrant proteins in mitochondria and renders the mutant cells more susceptible to apoptosis induced by oxidative stress. Furthermore, oxidative stress can modulate phosphorylation of mitochondrial proteins, which can affect metabolism in a number of diseases. Taken together, we suggest that oxidative stress-triggered protein modifications and defects in protein turnover play an important role in the pathogenesis and progression of mitochondrial diseases.
线粒体 DNA 的致病性突变和线粒体功能障碍与线粒体疾病有关。在这篇综述中，我们讨论了氧化应激引起的线粒体蛋白修饰，这些修饰可能导致线粒体疾病的病理生理学改变。我们发现，缺陷线粒体产生的过量 ROS 通过抑制 Sirt2 增加微管蛋白的乙酰化，导致 CPEO 综合征患者皮肤成纤维细胞中线粒体的核周分布。我们最近的工作表明，线粒体功能障碍诱导的氧化应激可以通过抑制携带突变 mtDNA 的人细胞中的泛素-蛋白酶体途径和蛋白酶活性来破坏蛋白质降解系统。这反过来又导致异常蛋白在线粒体中的积累，并使突变细胞更容易受到氧化应激诱导的凋亡。此外，氧化应激可以调节线粒体蛋白的磷酸化，这可以影响许多疾病中的代谢。总之，我们认为氧化应激触发的蛋白修饰和蛋白周转缺陷在线粒体疾病的发病机制和进展中起着重要作用。
