2. Academic Validation
  3. Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis

Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis

  • Cell Commun Signal. 2024 Jan 18;22(1):53. doi: 10.1186/s12964-024-01479-z.
Junchen Guo # 1 2,  Shanjie Wang # 1 2,  Xin Wan # 3,  Xiaoxuan Liu 1 2,  Zeng Wang 1 2,  Chenchen Liang 1 2,  Zhenming Zhang 1 2,  Ye Wang 1 2,  Miao Yan 1 2,  Pengyan Wu 1 2,  Shaohong Fang 4 5,  Bo Yu 6 7
Affiliations

Affiliations

  • 1 Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, 150000, China.
  • 2 The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150000, China.
  • 3 Department of Cardiology and Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
  • 4 Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, 150000, China. [email protected].
  • 5 The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150000, China. [email protected].
  • 6 Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, 150000, China. [email protected].
  • 7 The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150000, China. [email protected].
  • # Contributed equally.
PMID: 38238728 DOI: 10.1186/s12964-024-01479-z
Abstract

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial Ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with Ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and Ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase Reactive Oxygen Species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated Ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating Ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces Ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

Keywords

Ferroptosis; Ischemia reperfusion; KEAP1/NRF2; Methylmalonic acid; Oxidative stress.

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