Gerald Dorn

Equity Interest - Non-publicly traded entity ( e.g., stock, stock option, or other ownership interest)

THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE

The mitochondrial dynamism/fitness/biogenesis interactome in cardiac disease Dorn GW Project narrative Mitochondria constitute 30-40% of heart weight and metabolize fats, and proteins and sugars to generate ATP that powers cardiac contraction. Mitochondrial dysfunction contributes to cardiac hypertrophy, heart failure and myocardial infarction. These common heart diseases exhibit a mismatch between metabolic substrate availability and substrate preference: normal mitochondria prefer fats and proteins that most efficiently make ATP, whereas diseased mitochondria reserve fats and protein to repair heart damage and instead metabolize sugars. It was generally accepted that metabolic transitioning in hearts (from preferring fats to sugars or vice-versa) is simply a matter of genetic programming. However, we discovered that the heart must first rid itself of existing mitochondria before replacing them with those having a metabolic preference matching its condition. We identified the key factors responsible for removal, replacement and redistribution of mitochondria during metabolic transitions. Now, we are developing genetic and pharmacological means by which we can conditionally orchestrate and coordinate activities of these factors to match preferences of the heart's mitochondria to its available metabolic ?menu?. Moreover, by whole genome and exome sequencing we identified rare gene mutations that impair mitochondrial removal and replacement in patients with hypertrophy or heart failure. These studies provide a fresh understanding of cardiac metabolism and establish the foundation for a completely novel approach to managing heart disease by ?dialing in? mitochondrial metabolism to optimize cardiac contraction or repair.