Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia

Jie Yang; Mengjia Sun; Renzheng Chen; Xiaowei Ye; Boji Wu; Zhen Liu; Jihang Zhang; Xubin Gao; Ran Cheng; Chunyan He; Jingyu He; Xuhong Wang; Lan Huang

doi:10.1016/j.isci.2023.106328

Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia

iScience. 2023 Mar 5;26(4):106328. doi: 10.1016/j.isci.2023.106328. eCollection 2023 Apr 21.

Authors

Jie Yang^{1

2}, Mengjia Sun^{1

2}, Renzheng Chen^{1

2}, Xiaowei Ye^{1

2}, Boji Wu^{1

2}, Zhen Liu^{1

2}, Jihang Zhang^{1

2}, Xubin Gao^{1

2}, Ran Cheng^{1

2}, Chunyan He^{1

2}, Jingyu He^{1

2}, Xuhong Wang^{1

2}, Lan Huang^{1

2}

Affiliations

¹ Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
² Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

Abstract

Hypobaric hypoxia (HH) is the primary challenge at highland. Prolonged HH exposure impairs right cardiac function. Mitochondria-associated membrane (MAM) plays a principal role in regulating mitochondrial function under hypoxia, but the mechanism was unclear. In this study, proteomics analysis identified that PACS2, a key protein in MAM, and mitophagy were downregulated in HH. Metabolomics analysis indicated suppression of glucose and fatty acids aerobic oxidation in HH conditions. Cardiomyocyte Pacs2 deficiency disrupted MAM formation and endoplasmic reticulum (ER)-mitochondria calcium flux, further inhibiting mitophagy and energy metabolism in HH. Pacs2 overexpression reversed these effects. Cardiac-specific knockout of Pacs2 exacerbated mitophagy inhibition, cardiomyocyte injury, and right cardiac dysfunction induced by HH. Conditional knock-in of Pacs2 recovered HH-induced right cardiac impairment. Thus, PACS2 is essential for protecting cardiomyocytes through ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism. Our work provides insight into the mechanism of HH-induced cardiomyocyte injury and potential targets for maintaining the right cardiac function at the highland.

Keywords: Cardiovascular medicine; Metabolomics; Molecular biology; Physiology; Proteomics.