The mitochondrial dynamism/fitness/biogenesis interactome in cardiac disease Dorn GW II Abstract Cardiomyocyte mitochondria are essential providers of ATP that fuels contraction and normal or reparative cardiomyocyte growth. Observationally, cardiomyocyte utilization of metabolic substrates evolves during cardiac development from a fetal preference for carbohydrates to the normal adult preference for fatty acids. In adult hearts, pathological reversion toward mitochondrial utilization of carbohydrates is postulated to contribute to cardiac hypertrophy, heart failure and myocardial infarction. However, our grasp of specific mechanisms that direct cardiac substrate utilization is incomplete, and forced genetic production of cardiomyocyte mitochondria has not proven therapeutic in experimental models of heart disease. Our conceptual breakthrough was that cardiac metabolism is not determined by a ?master regulator?, but is directed by the interplay between mitochondrial dynamism, fitness and biogenesis. We posit that myocardial metabolic remodeling requires coordinated modulation of mitophagic mitochondrial removal, biogenic mitochondrial replacement and fusion/fission-mediated mitochondrial redistribution. By individually disrupting these pathways and defining the consequences on mitochondrial, cell and organ functioning we determined how these three processes are co-regulated and functionally-interdependent, therein defining a central role for Mfn2 as orchestrator of mitochondrial fate (i.e. retention vs removal). By engineering artificial Mfn2 mutations and studying damaging human Mfn2 mutations identified through DNA sequencing of cardiomyopathy cohorts we are learning how each major process within the interactome is internally fine-tuned through modulation of functionally opposing pairs. Specifically, Mfn-mediated mitochondrial fusion is opposed by Drp1- mediated mitochondrial fission; PGC1-mediated biogenesis of fatty acid-catabolizing mitochondria is opposed by PRC-mediated biogenesis of carbohydrate-catabolizing mitochondria; and mitochondrial replication is opposed by Parkin-mediated mitochondrial elimination. Based on these insights, which represent a convergence of the research aims of HL59888 (mito fusion) and HL128441 (mitophagy), we developed novel genetic and biochemical tools, namely Separation-of-Function mutant Mfn2 proteins and cell-permeant peptides, to specifically manipulate mitochondrial dynamism or mitophagy in vitro and in vivo. We will employ these new concepts and reagents to dissect the molecular mechanisms that drive metabolic remodeling in normal and diseased hearts, and to develop translatable means of optimally matching cardiac metabolism to pathophysiological status by ?dialing- in? mitochondrial quality and quantity via precision manipulations within the interactome.
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.
