Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction.

PGC-1-related coactivator (PRC) has a dual function in growth-regulated mitochondrial biogenesis and as a sensor of metabolic stress. PRC induction by mitochondrial inhibitors, intracellular ROS, or topoisomerase I inhibition orchestrates an inflammatory program associated with the adaptation to cellular stress. Activation of this program is accompanied by the coordinate expression of c-MYC, which is linked kinetically to that of PRC in response to multiple stress inducers.

Activation of a PGC-1-related coactivator (PRC)-dependent inflammatory stress program linked to apoptosis and premature senescence.

PGC-1-related coactivator (PRC), a growth-regulated member of the PGC-1 coactivator family, contributes to the expression of the mitochondrial respiratory apparatus. PRC also orchestrates a robust response to metabolic stress by promoting the expression of multiple genes specifying inflammation, proliferation, and metabolic reprogramming. Here, we demonstrate that this PRC-dependent stress program is activated during apoptosis and senescence, two major protective mechanisms against cellular dysfunction.

PGC-1-related coactivator (PRC), a sensor of metabolic stress, orchestrates a redox-sensitive program of inflammatory gene expression.

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.

Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria.

PRC, a member of the PGC-1 coactivator family, is responsive to serum growth factors and up-regulated in proliferating cells. Here, we investigated its in vivo role by stably silencing PRC expression with two different short hairpin RNAs (shRNA1 and shRNA4) that were lentivirally introduced into U2OS cells. shRNA1 transductants exhibited nearly complete knockdown of PRC protein, whereas shRNA4 transductants expressed PRC protein at approximately 15% of the control level.

PGC-1-related coactivator complexes with HCF-1 and NRF-2beta in mediating NRF-2(GABP)-dependent respiratory gene expression.

The PGC-1 family of regulated coactivators (PGC-1alpha, PGC-1beta, and PRC) plays an important role in directing respiratory gene expression in response to environmental signals. Here, we show that PRC and PGC-1alpha differ in their interactions with nuclear hormone receptors but are highly similar in their direct binding to several nuclear transcription factors implicated in the expression of the respiratory chain. Surprisingly, neither coactivator binds NRF-2(GABP), a multisubunit transcriptional activator associated with the expression of many respiratory genes.

PGC-1-related coactivator: immediate early expression and characterization of a CREB/NRF-1 binding domain associated with cytochrome c promoter occupancy and respiratory growth.

PGC-1-related coactivator (PRC) was initially characterized as a transcriptional coactivator that shares structural and functional features with PGC-1alpha. Both coactivators interact with nuclear respiratory factor 1 (NRF-1) and activate NRF-1 target genes required for respiratory chain expression. Here, we establish that PRC belongs to the class of immediate early genes that are rapidly induced in the transition from quiescence to proliferative growth.

Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators.

In vertebrates, mitochondrial DNA (mtDNA) transcription is initiated bidirectionally from closely spaced promoters, HSP and LSP, within the D-loop regulatory region. Early studies demonstrated that mtDNA transcription requires mitochondrial RNA polymerase and Tfam, a DNA binding stimulatory factor that is required for mtDNA maintenance. Recently, mitochondrial transcription specificity factors (TFB1M and TFB2M), which markedly enhance mtDNA transcription in the presence of Tfam and mitochondrial RNA polymerase, have been identified in mammalian cells.