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Published ahead of print on June 28, 2007, doi:10.1164/rccm.200701-161OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 768-777, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200701-161OC

Original Article

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

Douglas W. Haden1, Hagir B. Suliman2, Martha Sue Carraway1, Karen E. Welty-Wolf1, Abdelwahid S. Ali2, Hiroshi Shitara3, Hiromichi Yonekawa3 and Claude A. Piantadosi1

1 Department of Medicine and 2 Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; and 3 Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Douglas W. Haden, M.D., Box 3315, Room 0590, CR2 Building, Duke University Medical Center, Durham, NC 27710. E-mail: dhaden75{at}yahoo.com

Rationale: 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.

Objectives: To define the relationships between mitochondrial biogenesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis.

Methods: 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.

Measurements and Main Results: Peritonitis caused by 106 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-1{alpha}, 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.

Conclusions: This is the first demonstration that mitochondrial biogenesis restores oxidative metabolism in bacterial sepsis and is therefore an early and important prosurvival factor.

Key Words: gram-positive bacteria • biogenesis • oxidative stress


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Mitochondrial biogenesis has been described as an adaptive cellular response in conditions such as exercise and hormone exposure. Emerging data now suggest that mitochondrial biogenesis might play a role in inflammatory conditions.

What This Study Adds to the Field
Bacterial sepsis induces mitochondrial injury resulting in depressed metabolism and biogenesis restores mitochondrial content and function.

 

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