The biarylpyrazole compound AM251 alters mitochondrial physiology via proteolytic degradation of ERR?.

ABSTRACT: The orphan nuclear receptor estrogen-related receptor alpha (ERR?) directs the transcription of nuclear genes involved in energy homeostasis control and the regulation of mitochondrial mass and function. A crucial role for controlling ERR?-mediated target gene expression has been ascribed to the biarylpyrazole compound 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) through direct binding to and destabilization of ERR? protein. Here, we provide evidence that structurally related AM251 analogs also have negative impacts on ERR? protein levels in a cell-type-dependent manner while having no deleterious actions on ERR?. We show that these off-target cellular effects of AM251 are mediated by proteasomal degradation of nuclear ERR?. Cell treatment with the nuclear export inhibitor leptomycin B did not prevent AM251-induced destabilization of ERR? protein, whereas proteasome inhibition with MG132 stabilized and maintained its DNA-binding function, indicative of ERR? being a target of nuclear proteasomal complexes. NativePAGE analysis revealed that ERR? formed a ?220-kDa multiprotein nuclear complex that was devoid of ERR? and the coregulator peroxisome proliferator-activated receptor ? coactivator-1. AM251 induced SUMO-2,3 incorporation in ERR? in conjunction with increased protein kinase C activity, whose activation by phorbol ester also promoted ERR? protein loss. Down-regulation of ERR? by AM251 or small interfering RNA led to increased mitochondria biogenesis while negatively impacting mitochondrial membrane potential. These results reveal a novel molecular mechanism by which AM251 and related compounds alter mitochondrial physiology through destabilization of ERR?.

SUBMITTER: Krzysik-Walker SM 

PROVIDER: S-EPMC3533472 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature