Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 46, Issue 6, Pages 804-810Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2009.02.026
Keywords
Mitochondria; Nitric oxide; Ischemic preconditioning; Cardioprotection; Reperfusion injury
Categories
Funding
- NHLBI NIH HHS [R01 HL071158, R01 HL071158-07] Funding Source: Medline
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Mitochondria play a critical role in cardiac function, and are also increasingly recognized as end effectors for various cardioprotective signaling pathways. Mitochondria use oxygen as a substrate, so by default their respiration is inhibited during hypoxia/ischemia. However, at reperfusion a surge of oxygen and metabolic substrates into the cell is thought to lead to rapid reestablishment of respiration, a burst of reactive oxygen species (ROS) generation and mitochondrial Ca2+ overload. Subsequently these events precipitate opening of the mitochondrial permeability transition (PT) pore, which leads to myocardial cell death and dysfunction. Given that mitochondrial respiration is already inhibited during hypoxia/ischemia, it is somewhat surprising that many respiratory inhibitors can improve recovery from ischemia-reperfusion (IR) injury. In addition ischemic preconditioning (IPC), in which short non-lethal cycles of IR can protect against subsequent prolonged IR injury, is known to lead to endogenous inhibition of several respiratory complexes and glycolysis. This has led to a hypothesis that the wash-out of inhibitors or reversal of endogerrous inhibition at reperfusion may afford protection by facilitating a more gradual wake-up of mitochondrial function, thereby avoiding a burst of ROS and Ca2+ overload. This paper will review the evidence in support of this hypothesis, with a focus on inhibition of each of the mitochondrial respiratory complexes. (C) 2009 Elsevier Inc. All rights reserved.
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