Ji Suk Chang, Ph.D.
Project 5: Role of NT-PGC-1 alpha in mitochondrial biogenesis and function
Brown adipose tissue (BAT) regulates energy expenditure by thermogenesis and its activity is largely dependent on mitochondria that metabolize nutrients and generate energy in the form of ATP and heat. Mitochondrial mass and function are tightly regulated in response to physiological stimuli. This coordination is primarily mediated by the transcriptional coactivator, PGC-1α. Highly inducible PGC-1α integrates physiological stimuli into the nuclear transcription program by coactivating a variety of transcription factors that induce expression of nuclear gene-encoded mitochondrial proteins and mitochondrial transcription factor A (TFAM). This in turn promotes mitochondrial DNA replication and transcription in mitochondria.
We have uncovered that the PGC-1α gene also produces the C-termianally truncated but transcriptionally active protein named NT-PGC-1α in BAT. NT-PGC-1α is able to activate the nuclear transcription program of adaptive thermogenesis in adipose tissue. Furthermore, we have identified NT-PGC-1α in isolated mitochondria and its recruitment to the mitochondrial DNA. These findings have led us to hypothesize that NT-PGC-1α has dual role in the nucleus and mitochondria by directly regulating nuclear- and mitochondrial-encoded genes, respectively. We plan to identify PGC-1α- and NT-PGC-1α-dependent target genes in the nucleus to understand the full biological effects of both isoforms. We will also define a unique role of NT-PGC-1α in mitochondrial DNA transcription. By generation of NT-PGC-1α-specific knockout mice, we will examine the effect of specific loss of NT-PGC-1α function on adaptive mitochondrial biogenesis and function. Results from this proposed work will generate a better understanding of the specific role of NT-PGC-1α in adaptive mitochondrial biogenesis and function.