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  • G P also plays a critical role


    G6P also plays a critical role in regulating HK2 binding to mitochondria. Elevated levels of intracellular G6P weaken HK2 binding to mitochondria, causing the enzyme to translocate to the cytoplasm and facilitate anabolic glucose metabolism. Acidosis similarly induces HK2 translocation from mitochondria to cytoplasm [38].
    Regulation of glucose metabolism by HK during I/R During acute myocardial ischemia, melatonin receptor agonist glycolysis and glycogenolysis assume the central role for energy production when oxidative phosphorylation cannot occur because of a lack of oxygen. The shift to anaerobic metabolism entails rapid increases in glucose uptake, glycogenolysis, and glycolytic flux [39]. During severe ischemia, however, the accumulation of protons and glycolytic intermediates eventually inhibits glycolytic flux and anaerobic ATP production ceases after 20–30min [40], [41]. The relative contribution of the glycolytic/glycogenolytic pathway to energy production is highly dependent on the severity of ischemia, with virtually no change up to moderate ischemia (reduction of coronary flow by <75%) to virtually 100% during total global ischemia. In the moderate ischemia case, glucose uptake remains unchanged, but glucose metabolism is directed from oxidation to lactate production [42]. Increased glucose uptake during ischemia is further stimulated by insulin [43]. Promoting glucose metabolism with glucose and insulin has been used successfully to protect hearts from I/R injury [44], [45], although the clinical utility has been limited [46]. In the adult heart, the subcellular localization of HK2 shifts during ischemia [47] due to the dissociation of HK2, but not HKI, from the mitochondria to cytoplasm [30], [48], [49] in response to intracellular acidification and G6P accumulation [38]. Upon reperfusion after a period of ischemia, the activity of HK is increased in both the cytosolic and mitochondrial compartments [50], probably promoted by activation of Akt signaling via the RISK pathway. Under these conditions of Akt-enhanced HK2 binding to mitochondria, the heart is in a cardioprotected state. After IPC, HK2 dissociates more slowly during a subsequent prolonged ischemic episode, and this correlates with a slower rate of ATP depletion than during ischemia in unprotected hearts [51]. The maintained fraction of HK bound to mitochondria may also serve to facilitate glycolysis during reperfusion, which plays a critical role in recovery [52]. Given the multiple roles of HK in orchestrating metabolic, antioxidant and direct cell death effects from different subcellular locations, it is natural to ask whether the parallels between the cardioprotective status and HK binding to mitochondria are mere associations or are causally-linked. A growing body of evidence now supports a causal relationship. HK binding to mitochondria in cardiomyocytes has been demonstrated to confer profound protection against cell death by preventing mPTP opening [18], [53], [54]. Following prolonged ischemia, cytochrome c release, ROS production and infarct size at the reperfusion have been shown to parallel the amount of HK dissociated from mitochondria [38]. Similar to IPC, several cardioprotective interventions acting through the RISK pathway also increase mitochondrial HK activity and reduce I/R injury in isolated rat hearts [55]. The cardioprotective actions of the volatile anesthetics isoflurane and sevoflurane, whose effects are dependent on the PI3K/Akt signaling [56], have been shown to increase mitochondrial HK activity in in vivo adult rat hearts [57]. Akt has been shown to directly phosphorylate HK2, which inhibits G6P-mediated dissociation from mitochondria and increases cell viability after stress [18], [58]. Finally, disrupting HK2 binding to mitochondria with targeted peptides has been found to increase I/R injury and attenuate cardioprotection by IPC, and genetic reduction of HK2 levels in heterozygous HK2 knock-out mice increased susceptibility to I/R injury [59], [60].