title: Cardioprotection by metabolic shut-down and gradual wake-up.
abstract: 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 Ca(2+) 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 endogenous inhibition at reperfusion may afford protection by facilitating a more gradual wake-up of mitochondrial function, thereby avoiding a burst of ROS and Ca(2+) overload. This paper will review the evidence in support of this hypothesis, with a focus on inhibition of each of the mitochondrial respiratory complexes.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Burwell
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D042967:Electron Transport Complex I / Q000378:metabolism / Q000502:physiology; D042963:Electron Transport Complex II / Q000378:metabolism / Q000502:physiology; D014450:Electron Transport Complex III / Q000378:metabolism / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism / Q000502:physiology; D006019:Glycolysis / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology* / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology
chemical_list: D009569:Nitric Oxide; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III