Ubiquitin Proteasome-dependent Degradation of the Transcriptional Coactivator PGC-1α via the N-terminal Pathway

PGC-1 alpha is a potent, inducible transcriptional coactivator that exerts control on mitochondrial biogenesis and multiple cellular energy metabolic pathways. PGC-1 alpha levels are controlled in a highly dynamic manner reflecting regulation at both transcriptional and post-transcriptional levels. Here, we demonstrate that PGC-1 alpha is rapidly degraded in the nucleus (t(1/2) 0.3 h) via the ubiquitin proteasome system. An N-terminal deletion mutant of 182 residues, PGC182, as well as a lysine-less mutant form, are nuclear and rapidly degraded (t(1/2) 0.5 h), consistent with degradation via the N terminus-dependent ubiquitin sub-pathway. Both PGC-1 alpha and PGC182 degradation rates are increased in cells under low serum conditions. However, a naturally occurring N-terminal splice variant of 270 residues, NT-PGC-1 alpha is cytoplasmic and stable (t(1/2) > 7 h), providing additional evidence that PGC-1 alpha is degraded in the nucleus. These results strongly suggest that the nuclear N terminus-dependent ubiquitin proteasome pathway governs PGC-1 alpha cellular degradation. In contrast, the cellular localization of NT-PCG-1 alpha results in a longer-half-life and possible distinct temporal and potentially biological actions.