Peroxisome Proliferator-activated Receptor γ Co-activator 1-α as a Critical Co-activator of the Murine Hepatic Oxidative Stress Response and Mitochondrial Biogenesis in Staphylococcus aureus Sepsis

A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor γ co-activator 1-α (PPARGC-1-α or PGC-1α), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of...

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Published in:	The Journal of biological chemistry 2014-01, Vol.289 (1), p.41-52
Main Authors:	Cherry, Anne D., Suliman, Hagir B., Bartz, Raquel R., Piantadosi, Claude A.
Format:	Article
Language:	eng
Subjects:	Animals Antioxidants Co-activator 1 α Co-immunoprecipitation Gene Expression Regulation, Enzymologic - genetics Gene Regulation Liver - metabolism Liver - pathology Mice Mice, Mutant Strains Mitochondria, Liver - genetics Mitochondria, Liver - metabolism Mitochondria, Liver - pathology Mitochondrial Metabolism NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Oxidative Stress Peritonitis - genetics Peritonitis - metabolism Peritonitis - pathology Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Peroxisome Proliferator-activated Receptor γ Response Elements - genetics Sepsis Sepsis - genetics Sepsis - metabolism Sepsis - pathology Signal Transduction - genetics Staphylococcal Infections - genetics Staphylococcal Infections - metabolism Staphylococcal Infections - pathology Staphylococcus aureus Superoxide Dismutase (SOD) Superoxide Dismutase - biosynthesis Superoxide Dismutase - genetics Transcription Factors - genetics Transcription Factors - metabolism
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Summary:	A key transcriptional regulator of cell metabolism, the peroxisome proliferator-activated receptor γ co-activator 1-α (PPARGC-1-α or PGC-1α), also regulates mitochondrial biogenesis, but its role in antioxidant gene regulation is not well understood. Here, we asked whether genetic heterozygosity of PGC-1α modulates gene expression for the mitochondrial antioxidant enzyme SOD-2 during hepatic inflammatory stress. Using Staphylococcus aureus peritonitis in mice, we found significant Sod2 gene induction in WT mice, whereas PGC-1α heterozygotes (PGC-1α+/−) failed to augment Sod2 mRNA and protein levels. Impaired Sod2 regulation in PGC-1α+/− mice was accompanied by oxidative stress shown by elevated mitochondrial GSSG/GSH and protein carbonyls. In silico analysis of the mouse proximal Sod2 promoter region revealed consensus binding sites for the Nfe2l2 (Nrf2) transcription factor. Chromatin immunoprecipitation demonstrated diminished Nfe2l2 protein binding to the antioxidant response element promoter site proximal to the Sod2 start site in PGC-1α heterozygous mice, implicating PGC-1α in facilitation of Nfe2l2 DNA binding. Nuclear protein co-immunoprecipitation demonstrated an interaction between hepatic Nfe2l2 and PGC-1α in WT mice that was greatly reduced in PGC-1α+/− mice. The data indicate that PGC-1α promotes mitochondrial antioxidant enzyme expression through Nfe2l2-mediated SOD-2 expression in sepsis. The presence of this new PGC-1α-dependent signaling axis indicates that PGC-1α opposes mitochondrial oxidative stress by means of selective induction of one or more antioxidant response element-driven genes. By implication, exploitation of this axis could lead to new pharmacological interventions to improve the antioxidant defenses during oxidative stress-induced mitochondrial damage. PGC-1α regulates mitochondrial biogenesis, and may participate in antioxidant gene regulation. PGC-1α-deficient mice in sepsis demonstrated increased hepatocellular mitochondrial oxidative stress and impaired antioxidant enzyme induction, reflecting PGC-1α interaction with the ARE-dependent Nfe2l2 transcription factor and Sod2 activation. PGC-1α is critical to mitochondrial SOD-2 induction during hepatic inflammation. This novel pathway offers unique opportunities to mitigate oxidative mitochondrial damage.
ISSN:	0021-9258 1083-351X