This Article Full Text Full Text (PDF) All Versions of this Article: 200701-161OCv1 176/8/768    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haden, D. W. Articles by Piantadosi, C. A. Search for Related Content PubMed PubMed Citation Articles by Haden, D. W. Articles by Piantadosi, C. A.

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

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- 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 coactivator-1, 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.

 

Related articles in AJRCCM:

Powering Up Failed Organs

Mervyn Singer
AJRCCM 2007 176: 733-734. [Full Text]  

This article has been cited by other articles:

				T. H. Elsasser, T. J. Caperna, C-J. Li, S. Kahl, and J. L. Sartin Critical control points in the impact of the proinflammatory immune response on growth and metabolism J Anim Sci, April 1, 2008; 86(14_suppl): E105 - E125. [Abstract] [Full Text] [PDF]

				M. Singer Powering Up Failed Organs Am. J. Respir. Crit. Care Med., October 15, 2007; 176(8): 733 - 734. [Full Text] [PDF]