Latvian Institute of Organic Synthesis, Riga, Latvia; Riga Stradins University, Riga, Latvia.
Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ 1105, Amsterdam, the Netherlands.
Free Radic Biol Med. 2021 Mar;165:24-37. doi: 10.1016/j.freeradbiomed.2021.01.036. Epub 2021 Jan 21.
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.
心脏是代谢灵活性最高的器官，可以根据不同能量代谢状态下可用的底物来使用。心脏线粒体可以感知底物的可用性，并确保氧化磷酸化和心脏功能的效率。线粒体在心肌缺血/再灌注损伤中也起着至关重要的作用，在此过程中，它们直接参与产生 ROS 的病理生理机制。本综述探讨了能量代谢途径中 ROS 产生的机制，并重点介绍了不同底物的影响。我们描述了在葡萄糖、脂肪酸和三羧酸循环途径中缺血期间积累的主要代谢物。高血糖症在缺血/再灌注的急性应激条件下很常见，它通过激活 NADPH 氧化酶 2 增加细胞浆 ROS 浓度，并通过代谢过载和减少己糖激酶 II 与线粒体的结合增加线粒体 ROS。脂肪酸相关的 ROS 产生与脂肪酸通量增加和相应的长链酰基辅酶 A 积累有关。在缺氧/缺血期间积累的琥珀酸被认为是 ROS 的主要来源，而衣康酸作为琥珀酸脱氢酶抑制剂的作用正在显现。我们讨论了调节和抵消产生 ROS 的底物积累的策略，以及这一概念的治疗意义。
