Jespersen 2017 J Physiol
|Jespersen NR, Yokota T, Støttrup NB, Bergdahl A, Paelestik KB, Povlsen JA, Dela F, Bøtker HE (2017) Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion. J Physiol 595:3765-80.|
Abstract: Mitochondrial dysfunction plays a central role in ischaemia-reperfusion (IR) injury. Pre-ischaemic administration of aminooxyacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against IR injury, although the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischaemia and early reperfusion could preserve mitochondrial function at a later phase of reperfusion in the IR-injured heart to the same extent as ischaemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. In the present study, we show that pre-ischaemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR-injured isolated rat hearts. 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 the IR-injured heart. As a result, 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 appears to be different from that of IPC because 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 the IR-injured heart, at least in part, via metabolic regulation of TCA cycle intermediates in the mitochondria at the onset of reperfusion.
© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society. • Keywords: Heart, Ischemia-reperfusion, Malate-aspartate shuttle, Mitochondria, Oxidative stress, Amplex Red • Bioblast editor: Kandolf G • O2k-Network Lab: DK Copenhagen Dela F, DK Aarhus Boetker HE, JP Sapporo Yokota T, CA Montreal Bergdahl A, DK Copenhagen Larsen S
Labels: MiParea: Respiration, Pharmacology;toxicology
Stress:Ischemia-reperfusion, Oxidative stress;RONS Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS Pathway: F, N, S, NS, ROX HRR: Oxygraph-2k