Deletion of PINK1 Accelerates and Exacerbates High‐fat‐diet Induced Cardiomyopathy

Abstract

RationaleMitochondrial dysfunction is a central event in the development of diabetic cardiomyopathy. Damaged mitochondria are a major source of reactive oxygen species (ROS) and pro‐apoptotic factors. Therefore, selective removal of dysfunctional mitochondria via autophagy (i.e., mitophagy) is an important mechanism to maintain mitochondrial homeostasis and preserve cell viability. Although mitochondrial dysfunction is implicated in diabetic cardiomyopathy, the molecular mechanisms by which diabetes impairs mitochondrial function remain elusive. PTEN‐induced putative kinase 1 (PINK1), a mitochondrial serine/threonine‐protein kinase encoded by the Pink1 gene, protects cells from stress‐induced mitochondrial dysfunction by activating mitophagy pathway.ObjectiveThis study was designed to evaluate the role of PINK1 in the development of cardiomyopathy in mice fed with high fat diet (HFD).ResultsWe observed that PINK1 protein levels were markedly reduced in HFD‐treated mouse heart. HFD‐treated mouse developed obvious cardiomyopathy, demonstrated by impaired diastolic function, which was evidenced by a decreased E/A‐wave ratio (E‐wave and A‐wave represent the left ventricle early filling and atrial contraction filling, respectively). Moreover, ejection fraction and fractional shortening were all decreased, indicating an impaired systolic function. The cardiac dysfunction was concurrent with increased cardiac fibrosis and apoptotic cells. Pink1−/− mouse also exhibited abnormal cardiac structure and function. Importantly, PINK1 ablation accelerated the development of diastolic cardiac dysfunction, as evidenced by a decreased E/A ratio, and exacerbated cardiomyopathy, as revealed by decreased ejection fraction, fractional shortening, E/A ratio, cardiomyocyte apoptosis and cardiac fibrosis. Autophagy‐dependent clearance of mitochondria was drastically reduced with a much more pronounced effect in Pink1−/− mouse, resulting in the accumulation of damaged mitochondria in the hearts. Thus, HFD feeding caused more severe mitochondrial injury, ROS generation, and apoptotic cell death in Pink1−/− mouse.ConclusionTaken together, our results suggested that PINK1‐mediated mitophagy plays an important role in the development of HFD‐induced cardiomyopathy.Support or Funding InformationThis work is supported by NIH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.