January 22 2018
12:00 1100 TLSB
Center for Molecular Medicine
National Heart Lung and Blood Institute
Mitophagy as a regulator of cardiac function in physiological and pathophysiological conditions
A decline in mitochondrial quality has been associated with aging, neurodegenerative diseases and cardiovascular diseases. Mitophagy, a specialized autophagic pathway that mediates the lysosomal clearance of damaged mitochondria, is essential for mitochondrial quality control. Recent studies have demonstrated an important role for mitophagy in both developmental and disease-related metabolic transitioning of cardiac mitochondria. Thus, a better understanding of the physiological and pathological roles of cardiac mitophagy is critical for understanding the normal physiology of the heart, as well as potential spurring new potential treatments for a wide array of cardiovascular diseases.
Currently, our knowledge regarding mitophagy in the heart and the cardiomyocytes is limited. Establishing more reliable methods to monitor cardiac mitophagy would dramatically advance our understanding of the molecular signaling mechanisms of mitophagy. My studies provided the first robust assessment of in vivo mitophagy, and demonstrated that a transgenic mouse that expresses mt-Keima can provide direct in vivo measurements of cardiac mitophagic flux during both physiological and pathological conditions.
Furthermore, using genome-scale CRISPR-Cas9 knockout screening and high-content image-based screening, I identified pathways/compounds that modulate mitophagy. In particular, accumulation of ubiquitinated outer mitochondrial membrane proteins has been proposed to act as a signal for selective mitophagy. However, removal of ubiquitin is achieved by the action of resident mitochondrial deubiquitinases, most notably USP30. Therefore, the USP30 knockout mice were generated to investigate whether genetic deletion of USP30 was able to stimulate cardiac mitophagy, and whether deletion/inhibition of USP30 could modulate disease progression in animal models of heart failure.