Nicolaj Støttrup

Pre-ischemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischemia-reperfusion

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Mitochondrial dysfunction plays a central role in ischemia-reperfusion (IR) injury. The pre-ischemic administration of aminooxyacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against IR injury, but the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischemia and early reperfusion could preserve mitochondrial function at later phase of reperfusion in IR-injured heart to the same extent as ischemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. Here we showed that a pre-ischemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR-injured isolated rat hearts. The AOA treatment also attenuated the excessive emission of mitochondrial reactive oxygen species during state 3 with complex I-linked substrates during late reperfusion, which was consistent with reduced oxidative damage in IR-injured heart. As a result, the AOA treatment reduced infarct size after reperfusion. These protective effects of MAS inhibition on the mitochondria were similar to those of IPC. Intriguingly, the protection of mitochondrial function by AOA treatment seems different from that of IPC, since AOA treatment, but not IPC, downregulated myocardial tricarboxilic acid (TCA)-cycle intermediates at the onset of reperfusion. MAS inhibition thus preserved mitochondrial respiratory capacity and decreased mitochondrial oxidative stress during late reperfusion in IR-injured heart, at least in part, via metabolic regulation of TCA-cycle intermediates in the mitochondria at the onset of reperfusion. This article is protected by copyright. All rights reserved.

TidsskriftThe Journal of Physiology
Sider (fra-til)3765-3780
Antal sider16
StatusUdgivet - 15 jun. 2017

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