PGC-1 beta-regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERR alpha.
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.
Shao
Di
D
The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Liu
Yang
Y
Liu
Xiaojun
X
Zhu
Liuluan
L
Cui
Ying
Y
Cui
Anfang
A
Qiao
Aijun
A
Kong
Xingxing
X
Liu
Yong
Y
Chen
Quan
Q
Gupta
Nishith
N
Fang
Fude
F
Chang
Yongsheng
Y
D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D001678:Organelle Biogenesis; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D000097983:ERRalpha Estrogen-Related Receptor
D002352:Carrier Proteins; D051266:Nuclear Respiratory Factor 1; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C495633:NRF1 protein, human; C455622:PPARGC1B protein, human