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

作者：Xiaofang Zeng, Jing Sun, Famei Li, Liming Peng, Chenglong Zhang, Xiaowei Jiang, Lihuang Zha, Anandharajan Rathinasabapathy, Jun Ren, Zaixin Yu, Lin Wang, Xiangwei Liu · 发表于：Antioxidants and Redox Signaling · 年份：2024 · DOI：10.1089/ars.2023.0399 · 被引用次数：10 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Lysosomal Storage Disorders Research

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. 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. For the fir...