The role of PARKIN-mediated mitophagy in modulating hepatic insulin resistance. As more than 1 out of 3 American adults are obese and the rate continues to rise, new interventions must be developed to combat the excess intracellular lipid, insulin resistance, and increased mitochondrial dysfunction that occurs alongside obesity. Recently, a form of mitochondrial quality control called mitophagy, where damaged mitochondria are degraded through selective autophagy, was shown to be deficient in liver in the context of obesity. A key protein modulating mitophagy is the E3 ubiquitin ligase encoded by the Park2 gene, PARKIN. Studies designed in this proposal will determine how the specific loss of PARKIN-mediated mitophagy in liver affects whole-body and tissue-specific mitochondrial metabolism using a liver-specific PARKIN knockout model (LKO), combined with state of the art in vivo mitophagy reporter mt-keima mouse. Additionally, this proposal will explore specific post-translational modifications of ubiquitin that may contribute to reduced mitophagy in obese fatty liver by inhibiting PINK1-PARKIN-mediated mitophagy signaling. The above work will be carried out by Dr. Lia Edmunds under the supervision of Drs. Robert O'Doherty and Michael Jurczak in the Division of Endocrinology and Metabolism at the University of Pittsburgh. This proposal has been carefully crafted to allow Dr. Edmunds the opportunity to further develop as a research scientist and be able to submit a K award at the end of the two-year period. Through this award, she will broaden her scientific and technical knowledge base, generate data and develop new skills necessary to succeed as an independent investigator. These goals will be achieved by 1) engaging directly in the proposed research, 2) by meeting with her mentors regularly, and 3) completing proposed coursework and attending specific scientific meetings as outlined in Activities Planned under this Award. The Division of Endocrinology and Metabolism at the University of Pittsburgh provides an ideal environment to pursue the proposed training, and Drs. O'Doherty and Jurczak will provide extensive resources and knowledge in support of Dr. Edmunds' success.
The relationship between type 2 diabetes, insulin resistance, and excess hepatic lipids is incompletely understood, but data from human studies demonstrates that insulin resistance is strongly associated with mitochondrial dysfunction. Mitochondria quality control is maintained through a process called mitophagy, where defective mitochondria are selectively removed via the autophagy pathway. This study will determine (1) if loss of mitochondrial quality control affects hepatic mitochondrial metabolism and homeostasis and (2) if excess acetylation associated with over-nutrition plays a role in diminished mitophagic rates.
