Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Mitochondrial Research in Translational Medicine Mitochondrial respiratory dysfunction-elicited oxidative stress and posttranslational protein modification in mitochondrial diseases Yu-Ting Wu, 1 Shi-Bei Wu, 1 Wan-Yu Lee, 1 and Yau-Huei Wei 1,2 1 Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan. 2 Department of Medicine, Mackay Medical College, Sanjhih, Taipei, Taiwan Address for correspondence: Prof. Yau-Huei Wei, Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan. joeman@ym.edu.tw 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 perinu- clear 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. Keywords: mitochondrial disease; CPEO; oxidative stress; posttranslational protein modification; acetylation; ubiquitination Introduction Mitochondria support energy-requiring activities of the animal and human cells by ATP synthesis through respiration and oxidative phosphorylation (OXPHOS). Two genetic systems in the nucleus and mitochondria cooperate to assure normal function- ing of mitochondria, which play a critical role in the regulation of energy metabolism in human cells. Mitochondrial diseases are a group of disorders due to respiratory chain deficiency. They are character- ized by myopathy and generalized muscle weakness due to structural and biochemical abnormalities of mitochondria that frequently appear in the skeletal muscle of patients. Since 1988, it has been shown that deletion or mutation of mitochondrial DNA (mtDNA) occurs in the muscle of patients of mito- chondrial myopathy, which underscores the impor- tance of mitochondrial genetic defects in the patho- physiology of mitochondrial disorders. 1 A large portion of mitochondrial diseases are maternally inherited through point mutation or large-scale deletion of mtDNA. Although pathogenetic mu- tations of mtDNA and mitochondrial dysfunction have been shown to contribute to the pathogene- sis of mitochondrial diseases, the molecular mech- anism underlying the manifestation of diseases and the association between the clinical phenotype and genotype have remained ambiguous. Abundant evidence supports the notion that oxidative stress elicited by respiratory chain de- fects plays an important role in the pathogene- sis and progression of mitochondrial diseases and age-related disease. 2,3 In previous studies, we have doi: 10.1111/j.1749-6632.2010.05631.x Ann. N.Y. Acad. Sci. 1201 (2010) 147–156 c  2010 New York Academy of Sciences. 147