Abstract 849: Drp1-dependent Altered Mitochondrial Dynamics Contribute to Protein Aggregation and Mitochondrial Dysfunction in R120G αB-crystallin-induced Proteotoxicity

Abstract

Introduction: αB-crystallin (CryAB) is a chaperone protein that plays a pivotal role in the maintenance of the structural and mechanical integrity of the sarcomere. Mutation in αB-crystallin (CryAB R120G) causes sarcomere disorganization leading to protein aggregation. Accumulation of toxic protein aggregates causes cardiac contractile dysfunction and perturbed mitochondrial spatial organization. However, the role of mitochondria in the pathogenesis of protein aggregation-induced cardiomyopathies remain obscure. Objective: In this study, we investigated the role of mitochondrial dynamics and function in the development of R120G αB-crystallin induced cardiac proteotoxicity. Methods and Results: CryAB R120G Tg hearts showed accumulation of toxic protein aggregates resulting in disruption of the sarcomere structure, development of cardiomyocyte hypertrophy, and contractile dysfunction. Hearts obtained from CryAB R120G Tg mice showed increased expression and localization of Drp1 on the mitochondrial membrane. Alteration in the expression of mitochondrial dynamics regulatory proteins was observed at two months age when these mice exhibited normal cardiac morphometry and systolic function. Adenoviral-mediated expression of CryAB R120G in cardiomyocytes also showed increased mitochondrial fission, expression dependent inhibition of mitochondrial respiration and activation of cellular toxicity. Inhibition mitochondrial fission by Drp1 partial knockdown in CryABR120G expressing cardiomyocytes significantly decreased protein aggregation and improved mitochondrial respiration. Conclusion: Drp1-dependent excessive mitochondrial fission results in defects in mitochondrial respiration and accumulation of protein aggregates in CryABR120G expressing cardiomyocytes. Therefore, our study shows that maladaptive aberrant mitochondrial fission causes CryABR120G -induced mitochondrial dysfunction and cardiac proteotoxicity-associated cellular dysfunction.