Mitochondrial DNA mutations and oxidative damage in skeletal muscle of patients with chronic uremia

Paik Seong Lim, Yi Shing Ma, Yueh Mei Cheng, Henry Chai, Cheng Feng Lee, Tzu Ling Chen, Yau Huei Wei*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

27 引文 斯高帕斯(Scopus)

摘要

Abundant evidence has been gathered to suggest that mitochondrial DNA (mtDNA) sustains many more mutations and greater oxidative damage than does nuclear DNA in human tissues. Uremic patients are subject to a state of enhanced oxidative stress due to excess production of oxidants and a defective antioxidant defense system. This study was conducted to investigate mtDNA mutations and oxidative damage in skeletal muscle of patients with chronic uremia. Results showed that large-scale deletions between nucleotide position (np) 7,900 and 16,300 of mtDNA occurred at a high frequency in muscle of uremic patients. Among them, the 4,977-bp deletion (mtDNA4977) was the most frequent and most abundant large-scale mtDNA deletion in uremic skeletal muscle. The proportion of mtDNA4977 was found to correlate positively with the level of 8-hydroxy 2′-deoxyguanosine (8-OHdG) in the total DNA of skeletal muscle (r = 0.62, p < 0.05). Using long-range PCR and DNA sequencing, we identified and characterized multiple deletions of mtDNA in skeletal muscle of 16 of 19 uremic patients examined. The 8,041-bp deletion, which occurred between np 8035 and 16,075, was flanked by a 5-bp direct repeat of 5′-CCCAT-3′. Some of the deletions were found in more than 1 patient. On the other hand, we found that the mean 8-OHdG/105 dG ratio in the total cellular DNA of muscle of uremic patients was significantly higher than that of the controls (182.7 ± 63.6 vs. 50.9 ± 21.5, p =0.05). In addition, the mean 8-OHdG/105 dG ratio in muscle mtDNA of uremic patients was significantly higher than that in nuclear DNA (344.0 ± 56.9 vs. 146.3 ± 95.8, p =0.001). Moreover, we found that the average content of lipid peroxides in mitochondrial membranes of skeletal muscle of uremic patients was significantly higher than that of age-matched healthy subjects (23.76 ± 6.06 vs. 7.67 ± 0.95 nmol/mg protein; p < 0.05). The average content of protein carbonyls in the mitochondrial membranes prepared from uremic skeletal muscles was significantly higher than that in normal controls (24.90 ± 4.00 vs. 14.48 ± 1.13 nmol/mg protein; p < 0.05). Taken together, these findings suggest that chronic uremia leads to mtDNA mutations together with enhanced oxidative damage to DNA, lipids, and proteins of mitochondria in skeletal muscle, which may contribute to the impairment of mitochondrial bioenergetic function and to skeletal myopathy commonly seen in uremic patients.

原文英語
頁(從 - 到)549-560
頁數12
期刊Journal of Biomedical Science
9
發行號6
DOIs
出版狀態已出版 - 2002
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