2. Academic Validation
  3. A Metabolomics-Based Study on NMDAR-Mediated Mitochondrial Damage through Calcium Overload and ROS Accumulation in Myocardial Infarction

A Metabolomics-Based Study on NMDAR-Mediated Mitochondrial Damage through Calcium Overload and ROS Accumulation in Myocardial Infarction

  • Front Biosci (Landmark Ed). 2023 Jul 19;28(7):140. doi: 10.31083/j.fbl2807140.
Yuanyuan Wang 1,  Li He 1 2,  Dan Du 3,  Zeyi Cheng 1,  Chaoyi Qin 1 2
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, West China Hospital, Sichuan University, 610007 Chengdu, Sichuan, China.
  • 2 Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, 610007 Chengdu, Sichuan, China.
  • 3 West China - Washington Mitochondria and Metabolism Center, West China Hospital, Sichuan University, 610007 Chengdu, Sichuan, China.
PMID: 37525913 DOI: 10.31083/j.fbl2807140
Abstract

Background: Coronary artery disease is a leading public health problem. However, the mechanisms underlying mitochondrial damage remain unclear. The present study verified and explored the novel mechanisms underlying ischemic injury based on a metabolomic analysis.

Methods: Mouse models of acute myocardial infarction were established, and serum samples were collected for targeted liquid chromatography with tandem mass spectrometry analysis. Based on metabolomic analyses, the N-methyl-d-aspartic acid receptor (NMDAR)-related calcium transporting signaling pathway was selected. Primary cardiomyocyte cultures were used, and N-methyl-d-aspartic acid (NMDA) was used as an agonist to confirm the role of NMDAR in ischemic injury. In addition, Bax, Bcl-2, mitochondrial calcium, potential, and mitochondrial Reactive Oxygen Species accumulation were used to explore the role of NMDAR in mitochondrial damage-induced Apoptosis.

Results: Glutamate-related metabolism was significantly altered following in acute myocardial infarction. NMDA induces Apoptosis under hypoxic conditions NMDAR was translocated to the mitochondrial-related membrane after activation, and its mitochondrial expression was significantly increased (p < 0.05). Mitochondrial damage-induced Apoptosis was significantly inhibited by a selective NDMAR antagonist (p < 0.05), while Bax expression was remarkably decreased and Bcl-2 expression was increased (p < 0.05). To further explore the mechanism of NMDAR, mitochondrial calcium, membrane potential, and Reactive Oxygen Species were detected. With NMDAR inhibition under hypoxic conditions, mitochondrial morphology and function were preserved (p < 0.05).

Conclusions: Our metabolomic study identified NMDAR as a promising target. In conclusion, our study provides solid data for further studies of the role of NMDAR in cardiovascular diseases and a promising target to interfere with Apoptosis in acute myocardial infarction.

Keywords

NMDAR; calcium overload; metabolomics; mitochondrial damage; myocardial infarction.

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