Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations

With age. mitochondrial DNA mutations and oxidative stress increase, leadin g to the hypothesis that the production of reactive oxygen species causes t he pathogenic effects of mitochondrial DNA mutations. We tested this hypoth esis using transgenic mice that develop cardiomyopathy due to the accumulat ion of mitochondrial DNA mutations specifically in the heart. Surprisingly, the mechanism of pathogenesis does not involve increased oxidative stress. The amounts of DNA and protein oxidative adducts are not elevated in the t ransgenic heart. Neither are signs of increased oxidative stress detected b y measurements of enzyme function or oxidative defense systems. Rather, we find that the mitochondrial DNA mutations induce a cytoprotective response including increases in the levels of Bcl-2 and Bfl-1, pro-survival proteins that inhibit apoptosis. and atrial natriuretic factor. Bcl-2 is elevated i n nearly all cardiomyocytes before the onset of dilated cardiomyopathy. The se results raise the possibility that a signaling pathway between the mitoc hondrion and the nucleus mediates the pathogenic effect of mitochondrial DN A mutations. (C) 2001 Elsevier Science B.V. All rights reserved.