title: Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system.
abstract: Respiratory function of mitochondria is compromised in aging human tissues and severely impaired in the patients with mitochondrial disease. A wide spectrum of mitochondrial DNA (mtDNA) mutations has been established to associate with mitochondrial diseases. Some of these mtDNA mutations also occur in various human tissues in an age-dependent manner. These mtDNA mutations cause defects in the respiratory chain due to impairment of the gene expression and structure of respiratory chain polypeptides that are encoded by the mitochondrial genome. Since defective mitochondria generate more reactive oxygen species (ROS) such as O2- and H2O2 via electron leak, we hypothesized that oxidative stress is a contributory factor for aging and mitochondrial disease. This hypothesis has been supported by the findings that oxidative stress and oxidative damage in tissues and culture cells are increased in elderly subjects and patients with mitochondrial diseases. Another line of supporting evidence is our recent finding that the enzyme activities of Cu,Zn-SOD, catalase and glutathione peroxidase (GPx) decrease with age in skin fibroblasts. By contrast, Mn-SOD activity increases up to 65 years of age and then slightly declines thereafter. On the other hand, we observed that the RNA, protein and activity levels of Mn-SOD are increased two- to three-fold in skin fibroblasts of the patients with CPEO syndrome but are dramatically decreased in patients with MELAS or MERRF syndrome. However, the other antioxidant enzymes did not change in the same manner. The imbalance in the expression of these antioxidant enzymes indicates that the production of ROS is in excess of their removal, which in turn may elicit an elevation of oxidative stress in the fibroblasts. Indeed, it was found that intracellular levels of H2O2 and oxidative damage to DNA and lipids in skin fibroblasts from elderly subjects or patients with mitochondrial diseases are significantly increased as compared to those of age-matched controls. Furthermore, Mn-SOD or GPx-1 gene knockout mice were found to display neurological disorders and enhanced oxidative damage similar to those observed in the patients with mitochondrial disease. These observations are reviewed in this article to support that oxidative stress elicited by defective respiratory function and impaired antioxidant enzyme system plays a key role in the pathophysiology of mitochondrial disease and human aging.
authors.affiliation: Department of Biochemistry, National Yang-Ming University, Taipei, Taiwan, ROC. joeman@ym.edu.tw
authors.forename: Y H
authors.initials: YH
authors.lastname: Wei
authors.forename: C Y
authors.initials: CY
authors.lastname: Lu
authors.forename: C Y
authors.initials: CY
authors.lastname: Wei
authors.forename: Y S
authors.initials: YS
authors.lastname: Ma
authors.forename: H C
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D016166:Free Radical Scavengers / Q000378:metabolism*; D006801:Humans; D017241:MELAS Syndrome / Q000378:metabolism; D017243:MERRF Syndrome / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000503:physiopathology; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D010088:Oxidoreductases