Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis.
The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure.To define the relationships between mitochondrial biogenesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis.We developed a murine model of fibrin clot peritonitis, using S. aureus. The model yielded dose-dependent decreases in survival and resting energy expenditure, allowing us to study recovery from sublethal sepsis.Peritonitis caused by 10(6) colony-forming units of S. aureus induced a low tumor necrosis factor-alpha state and minimal hepatic cell death, but activated prosurvival protein kinase A, B, and C sequentially over 3 days. Basal metabolism by indirect calorimetry was depressed because of selective mitochondrial oxidative stress and subsequent loss of mitochondrial DNA copy number. During recovery, mitochondrial biogenesis was strongly activated by regulated expression of the requisite nuclear respiratory factors 1 and 2 and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha, as well as by repression of the biogenesis suppressor nuclear receptor interacting protein-140. Biogenesis reconstituted mitochondrial DNA copy number and transcription, and restored basal metabolism without significant hepatocellular proliferation. These events dramatically increased hepatic mitochondrial density in transgenic mice expressing mitochondrially targeted green fluorescent protein.This is the first demonstration that mitochondrial biogenesis restores oxidative metabolism in bacterial sepsis and is therefore an early and important prosurvival factor.
Haden, DW; Suliman, HB; Carraway, MS; Welty-Wolf, KE; Ali, AS; Shitara, H; Yonekawa, H; Piantadosi, CA
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