PGC-1-related Coactivator (PRC), a Sensor of Metabolic Stress, Orchestrates a Redox-sensitive Program of Inflammatory Gene Expression

Abstract

PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor that activates many nuclear genes specifying mitochondrial respiratory function. Stable PRC silencing in U2OS cells results in a complex phenotype typical of mitochondrial dysfunction including abundant abnormal mitochondria, reduced respiratory subunit expression, diminished respiratory enzymes and ATP levels, and elevated lactate production. The PRC response to metabolic stress was investigated by subjecting cells to metabolic insults including treatment with the uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP), expression of a dominant negative allele of nuclear respiratory factor 1 (NRF-1), and glucose deprivation. These treatments led to constitutively elevated PRC protein levels, a departure from its normal transient expression upon the initiation of cell growth. A microarray screen identified 45 genes that require PRC for their induction by CCCP. A subset of these genes specific to inflammation and cell stress was also induced by dominant negative NRF-1 and by glucose deprivation, suggesting that diverse metabolic insults converge on the same PRC-dependent inflammatory program. The PRC-dependent inflammatory response was inhibited by N-acetylcysteine, suggesting that PRC may contribute to the inflammatory microenvironment linked to oxidant signaling. The induction of this PRC-dependent program may be an early event in adaptations linked to cancer and degenerative diseases.