Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations.
With age, mitochondrial DNA mutations and oxidative stress increase, leading to the hypothesis that the production of reactive oxygen species causes the pathogenic effects of mitochondrial DNA mutations. We tested this hypothesis using transgenic mice that develop cardiomyopathy due to the accumulation 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 transgenic heart. Neither are signs of increased oxidative stress detected by 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 in nearly all cardiomyocytes before the onset of dilated cardiomyopathy. These results raise the possibility that a signaling pathway between the mitochondrion and the nucleus mediates the pathogenic effect of mitochondrial DNA mutations.
Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
J L
JL
Mott
D
D
Zhang
M
M
Stevens
S
S
Chang
G
G
Denniger
H P
HP
Zassenhaus
D000818:Animals; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D014158:Transcription, Genetic; D014452:Ubiquitins / Q000378:metabolism; D015854:Up-Regulation
D017931:DNA Primers; D004272:DNA, Mitochondrial; D007506:Iron-Sulfur Proteins; D014452:Ubiquitins