Changhan David Lee, Ph.D.
Leonard Davis School of Gerontology
University of Southern California
USC Norris Comprehensive Cancer Center
USC Research Center for Liver Diseases

ABSTRACT
Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. We previously identified a peptide encoded in the mitochondrial DNA, named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c). MOTS-c regulates insulin sensitivity and metabolic homeostasis in an AMPK- and SIRT1-dependent manner. Our recent studies show that MOTS-c rapidly and dynamically translocates to the nucleus to regulate the nuclear genome in response to cellular stress. Within the nucleus, MOTS-c interacts with stress-responsive transcription factors and can bind to chromatin to regulate a range of adaptive gene expression. In mice, MOTS-c expression is age- and tissue-dependent. Further, MOTS-c treatment reversed age-dependent insulin resistance and significantly improved physical capacity and metabolic homeostasis in aged mice and had a considerable impact on lifespan. In humans, a centenarian-related haplogroup in a Japanese population is linked to functional MOTS-c residue variant. Our data suggest the integration of mitochondrial and the nucleus at the genetic level and that the close intergenomic communication regulates cellular homeostasis and aging.

Host: Young Jang