Parkin Insufficiency Accentuates High-Fat Diet–Induced Cardiac Remodeling and Contractile Dysfunction Through VDAC1-Mediated Mitochondrial Ca2+ Overload


Wu N. N. , Bi Y., Ajoolabady A., You F., Sowers J., Wang Q., ...More

JACC: Basic to Translational Science, vol.7, no.8, pp.779-796, 2022 (Peer-Reviewed Journal) identifier identifier

  • Publication Type: Article / Article
  • Volume: 7 Issue: 8
  • Publication Date: 2022
  • Doi Number: 10.1016/j.jacbts.2022.03.007
  • Journal Name: JACC: Basic to Translational Science
  • Journal Indexes: Science Citation Index Expanded, Scopus, BIOSIS, EMBASE, Directory of Open Access Journals
  • Page Numbers: pp.779-796
  • Keywords: Ca2+ overload, heart, high-fat diet, mitochondria, Parkin, VDAC1

Abstract

© 2022 The AuthorsMitochondrial Ca2+ overload contributes to obesity cardiomyopathy, yet mechanisms that directly regulate it remain elusive. The authors investigated the role of Parkin on obesity-induced cardiac remodeling and dysfunction in human hearts and a mouse model of 24-week high-fat diet (HFD) feeding. Parkin knockout aggravated HFD-induced cardiac remodeling and dysfunction, mitochondrial Ca2+ overload, and apoptosis without affecting global metabolism, blood pressure, and aortic stiffness. Parkin deficiency unmasked HFD-induced decline in voltage-dependent anion channel (VDAC) type 1 degradation through the ubiquitin-proteasome system but not other VDAC isoforms or mitochondrial Ca2+ uniporter complex. These data suggest that Parkin-mediated proteolysis of VDAC type 1 is a promising therapeutic target for obesity cardiomyopathy.