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

Ne N Wu; Yaguang Bi; Amir Ajoolabady; Fei You; James Sowers; Qiurong Wang; Asli F Ceylan; Yingmei Zhang; Jun Ren

doi:10.1016/j.jacbts.2022.03.007

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

JACC Basic Transl Sci. 2022 Aug 22;7(8):779-796. doi: 10.1016/j.jacbts.2022.03.007. eCollection 2022 Aug.

Authors

Ne N Wu¹, Yaguang Bi¹, Amir Ajoolabady¹, Fei You², James Sowers³, Qiurong Wang¹, Asli F Ceylan⁴, Yingmei Zhang¹, Jun Ren¹

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Cardiology, Xi'an Central Hospital, Xi'an, China.
³ Diabetes and Cardiovascular Research Center, University of Missouri Columbia, Columbia, Missouri, USA.
⁴ Faculty of Medicine, Department of Medical Pharmacology, Ankara Yildirim Beyazit University, Bilkent, Ankara, Turkey.

Abstract

Mitochondrial 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.

Keywords: AMCM, adult murine cardiomyocyte; BP, blood pressure; Ca2+ overload; HFD, high-fat diet; LFD, low-fat diet; LV, left ventricular; MCU, mitochondrial Ca2+ uniporter; PA, palmitic acid; Parkin; ROS, reactive oxygen species; TR90, time to 90% relengthening; VDAC, voltage-dependent anion channel; VDAC1; WT, wild-type; heart; high-fat diet; mPTP, mitochondrial permeability transition pore; mitochondria.