Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function

Abstract

Abstract βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, roles of βII spectrin in cardiac contractile function and post-myocardial infarction pathological remodeling remain unclear. Here, we uncovered that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction. Consistently, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after ischemia/reperfusion (I/R) injury. Cardiac-specific βII spectrin deletion results in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis. Moreover, deletion of βII spectrin in the adult heart exacerbated I/R-induced cardiomyocyte death and heart failure, while restoration of βII spectrin expression by adenoviral saRNA delivery in the heart reduced I/R injury. IP–LC–MS/MS and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin interacted with mitochondrial complex I to mediate its assembly by crosslinking with actin filaments (F-actin) to maintain F-actin stability. These findings identify βII spectrin as an essential mitochondrial cytoskeletal element for preserving mitochondrial homeostasis and cardiac function.