PGC-1β-Regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERRα

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) coactivator-1 beta (PGC-1 beta) is a well-established regulator of the beta-oxidation of fatty acids and the oxidative phosphorylation in mitochondria. However, the underlying mechanism of PGC-1 beta action remains elusive. This study reveals that PGC-1 beta is highly induced during myogenic differentiation and knockdown of endogenous PGC-1 beta by siRNA leads to a decrease in the expression of several mitochondria-related genes. In consistence, the over-expression of PGC-1 beta stimulates its target genes such as cytochrome c, ATP synthase beta and ALAS-1 by its interaction with two transcriptional factors, NRF-1 and ERR alpha. The deletion or mutation of NRF-1 and/or ERR alpha binding sites in target gene promoters attenuates their activation by PGC-1 beta. Moreover, inhibition of NRF-1 or ERR alpha by siRNA ablated the aforesaid function of PGC-1 beta and compromised the oxidative phosphorylation and mitochondrial biogenesis. Taken together, these results confirm the direct interaction of NRF-1 and ERR alpha with PGC-1 beta, and their participation in mitochondrial biogenesis and respiration. (C) 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved.