Mitochondrial abnormalities in tumor necrosis factor-alpha-induced heart failure are associated with impaired DNA repair activity.
نویسندگان
چکیده
BACKGROUND Recent studies suggest that mutations in cardiac mitochondrial DNA (mtDNA) may contribute to the development of dilated cardiomyopathy. The mechanisms that regulate those mutations, however, remain undefined. Thus, we studied cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF-alpha (TNF1.6 mice). METHODS AND RESULTS We studied mtDNA repair by measuring the uracil DNA glycosylase (mtUDG) and base excision repair activities. mtDNA damage was assessed by Southern blot of Fpg protein-digested mtDNA. Mitochondrial ultrastructural changes were examined by electron microscopy, and function by cytochrome c oxidase and succinate dehydrogenase activity assays. The results showed that both mtUDG and base excision repair activities were significantly reduced in TNF1.6 mouse heart. Fpg-sensitive sites were markedly increased in TNF1.6 mouse cardiac mtDNA, suggesting increased mtDNA damage. Mitochondrial function as demonstrated by cardiac cytochrome c oxidase activity was also markedly reduced. Cardiac ATP content was not changed, however, suggesting a shift from oxidative phosphorylation to glycolysis, as shown by increased LDH and ALT activities and lactate/pyruvate ratio. Ultrastructurally, the TNF1.6 mouse cardiac mitochondria became irregular in shape and smaller, and the cristae were decreased and appeared disorganized, with breaks. CONCLUSIONS These results suggest that mtDNA mutations and mitochondrial structural and functional alterations in TNF-alpha-induced heart failure may be associated with reduced mtDNA repair activity, and the pathophysiological effects of TNF-alpha on the heart may be mediated, at least in part, through these changes in mitochondria.
منابع مشابه
Mitochondrial Abnormalities in Tumor Necrosis Factor- –Induced Heart Failure Are Associated With Impaired DNA Repair Activity
Background—Recent studies suggest that mutations in cardiac mitochondrial DNA (mtDNA) may contribute to the development of dilated cardiomyopathy. The mechanisms that regulate those mutations, however, remain undefined. Thus, we studied cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF(TNF1.6 mic...
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ورودعنوان ژورنال:
- Circulation
دوره 104 20 شماره
صفحات -
تاریخ انتشار 2001