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  3. MFN2-mediated mitochondrial fusion facilitates acute hypobaric hypoxia-induced cardiac dysfunction by increasing glucose catabolism and ROS production

MFN2-mediated mitochondrial fusion facilitates acute hypobaric hypoxia-induced cardiac dysfunction by increasing glucose catabolism and ROS production

  • Biochim Biophys Acta Gen Subj. 2023 Jun 16;130413. doi: 10.1016/j.bbagen.2023.130413.
Ailin Yang 1,  Lifei Guo 1,  Yanfang Zhang 1,  Chenjin Qiao 1,  Yijin Wang 1,  Jiaying Li 1,  Min Wang 2,  Jinliang Xing 3,  Fei Li 4,  Lele Ji 5,  Haitao Guo 6,  Ru Zhang 7
Affiliations

Affiliations

  • 1 College of Life Sciences, Northwest University, Xi'an 710069, China.
  • 2 College of Life Sciences, Northwest University, Xi'an 710069, China; Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 3 State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
  • 4 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 5 Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: jilele@fmmu.edu.cn.
  • 6 State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: haitaoguo@fmmu.edu.cn.
  • 7 State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: zhang1ru123@163.com.
PMID: 37331409 DOI: 10.1016/j.bbagen.2023.130413
Abstract

Background: Rapid ascent to high-altitude environment which is characterized by acute hypobaric hypoxia (HH) may increase the risk of cardiac dysfunction. However, the potential regulatory mechanisms and prevention strategies for acute HH-induced cardiac dysfunction have not been fully clarified. Mitofusin 2 (MFN2) is highly expressed in the heart and is involved in the regulation of mitochondrial fusion and cell metabolism. To date, however, the significance of MFN2 in the heart under acute HH has not been investigated.

Methods and results: Our study revealed that MFN2 upregulation in hearts of mice during acute HH led to cardiac dysfunction. In vitro experiments showed that the decrease in oxygen concentration induced upregulation of MFN2, impairing cardiomyocyte contractility and increasing the risk of QT prolongation. Additionally, acute HH-induced MFN2 upregulation promoted glucose catabolism and led to excessive mitochondrial Reactive Oxygen Species (ROS) production in cardiomyocytes, ultimately resulting in decreased mitochondrial function. Furthermore, co-immunoprecipitation (co-IP) and mass spectrometry analyses indicated that MFN2 interacted with the NADH-ubiquinone oxidoreductase 23 kDa subunit (NDUFS8). Specifically, acute HH-induced MFN2 upregulation increased NDUFS8-dependent complex I activity.

Conclusions: Taken together, our studies provide the first direct evidence that MFN2 upregulation exacerbates acute HH-induced cardiac dysfunction by increasing glucose catabolism and ROS production.

General significance: Our studies indicate that MFN2 may be a promising therapeutic target for cardiac dysfunction under acute HH.

Keywords

Acute hypobaric hypoxia; Cardiac function; Glucose catabolism; MFN2; Mitochondrial fusion; ROS production.

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