Beclin 1 Haploinsufficiency Ameliorates High-Fat Diet-Induced Myocardial Injury via Inhibiting Alternative Mitophagy

Xiaofang Zeng; Jing Sun; Famei Li; Liming Peng; Chenglong Zhang; Xiaowei Jiang; Lihuang Zha; Anandharajan Rathinasabapathy; Jun Ren; Zaixin Yu; Lin Wang; Xiangwei Liu

doi:10.1089/ars.2023.0399

Beclin 1 Haploinsufficiency Ameliorates High-Fat Diet-Induced Myocardial Injury via Inhibiting Alternative Mitophagy

Antioxid Redox Signal. 2024 Mar 5. doi: 10.1089/ars.2023.0399. Online ahead of print.

Authors

Xiaofang Zeng^{1

2

3}, Jing Sun^{1

3}, Famei Li⁴, Liming Peng¹, Chenglong Zhang¹, Xiaowei Jiang¹, Lihuang Zha¹, Anandharajan Rathinasabapathy⁵, Jun Ren^{6

7}, Zaixin Yu^{1

3}, Lin Wang⁷, Xiangwei Liu^{1

3}

Affiliations

¹ Department of Cardiology, Central South University, Changsha, China.
² Department of Rheumatology, Central South University, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
⁵ Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁶ Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China.
⁷ Department of Geriatrics, Xijing Hospital, The Air Force Military Medical University, Xi'an, China.

PMID: 38251672
DOI: 10.1089/ars.2023.0399

Abstract

Aims: Mitochondrial homeostasis is essential for maintaining redox balance. Besides canonical autophagy, Rab9-dependent alternative autophagy is a crucial mechanism in metabolic cardiomyopathy. Here, we aim to investigate the role of alternative mitophagy and Beclin 1 haploinsufficiency (Beclin 1^+/-) in high-fat diet (HFD)-induced metabolic cardiomyopathy. Results: Twenty-four-week HFD impaired glucose tolerance and cardiomyocyte contraction in wild-type mice, both of which were rescued in Beclin 1^+/- mice. Beclin 1 haploinsufficiency had little effect on the conventional autophagy mediators (ATG5, LC3 II/LC3 I) but further upregulated Rab9 expression, a marker of alternative autophagy, in response to HFD challenge. Furthermore, either the inhibition of alternative autophagy or Beclin 1 haploinsufficiency abolished palmitic acid (PA)-induced cardiomyocyte contractile anomalies. In vitro, PA overactivated mitophagy, resulting in decreased mitochondrial content in H9C2 cells. These aberrations were alleviated in cells deficient in alternative autophagy but not in cells deficient in conventional autophagy. Mechanistically, HFD promoted reactive oxygen species (ROS) production, activated Rab9-dependent alternative mitophagy, and inhibited mitochondrial biosynthesis. Beclin 1^+/- rescued HFD-induced ROS overflow, mitochondrial biogenesis impairment, and prevented Rab9 translocation from the cytoplasm to the mitochondria, thereby inhibiting Rab9-mediated mitophagy overactivation. Innovation: For the first time, this study suggests that prolonged alternative mitophagy exacerbates chronic HFD-induced cardiac dysfunction and supports the protective role of Beclin 1 haploinsufficiency in metabolic cardiomyopathy. This provides additional evidence for a target-based pharmacological intervention. Conclusion: Beclin 1 haploinsufficiency protects against HFD-induced cardiac dysfunction by inhibiting Rab9-dependent alternative mitophagy and ROS production, while promoting mitochondrial biogenesis. Modulating Beclin 1 expression holds promise in preventing chronic HFD-related cardiomyopathy.

Keywords: Beclin 1; Rab9; alternative autophagy; metabolic cardiomyopathy; mitophagy.