Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury

Maija Dambrova (Coresponding Author), Coert J. Zuurbier, Vilmante Borutaite, Edgars Liepinsh, Marina Makrecka-Kuka

Research output: Contribution to journalArticlepeer-review

Abstract

The heart is the most metabolically flexible organ with respect to the use of substrates available in different states of energy metabolism. Cardiac mitochondria sense substrate availability and ensure the efficiency of oxidative phosphorylation and heart function. Mitochondria also play a critical role in cardiac ischemia/reperfusion injury, during which they are directly involved in ROS-producing pathophysiological mechanisms. This review explores the mechanisms of ROS production within the energy metabolism pathways and focuses on the impact of different substrates. We describe the main metabolites accumulating during ischemia in the glucose, fatty acid, and Krebs cycle pathways. Hyperglycemia, often present in the acute stress condition of ischemia/reperfusion, increases cytosolic ROS concentrations through the activation of NADPH oxidase 2 and increases mitochondrial ROS through the metabolic overloading and decreased binding of hexokinase II to mitochondria. Fatty acid-linked ROS production is related to the increased fatty acid flux and corresponding accumulation of long-chain acylcarnitines. Succinate that accumulates during anoxia/ischemia is suggested to be the main source of ROS, and the role of itaconate as an inhibitor of succinate dehydrogenase is emerging. We discuss the strategies to modulate and counteract the accumulation of substrates that yield ROS and the therapeutic implications of this concept.

Original languageEnglish
Pages (from-to)24-37
Number of pages14
JournalFree Radical Biology and Medicine
Volume165
DOIs
Publication statusPublished - Mar 2021

Keywords

  • Cardiac injury
  • Energy metabolism
  • Ischemia/reperfusion
  • Long-chain acylcarnitines
  • Mitochondria
  • Reactive oxygen species
  • Succinate

Field of Science

  • 3.1 Basic medicine
  • 1.6 Biological sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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