Mitochondrial KATP channels attenuate anoxic NMDAR currents via regulation of the mitochondrial Ca2+ uniporter in the western painted turtle

Abstract

Unlike anoxia‐sensitive mammals the western painted turtle survives prolonged periods of anoxia. Likely key is the ability to acutely decrease N‐methyl‐D‐aspartate receptor (NMDAR) activity with the onset of anoxia. Recently, we have shown that mitochondrial KATP channels (mKATP) regulate NMDARs in the anoxic turtle cortex via a Ca2+‐based mechanism. We hypothesized that mKATP activation in anoxia partially uncouples the mitochondrial membrane potential (Δψm), reducing the activity of the Ca2+ uniporter and thereby altering cellular Ca2+ homeostasis and subsequently NMDAR activity. NMDAR activity was measured using the whole‐cell patch‐clamp technique and cellular Ca2+ was measured fluorescently. Mitochondrial uncoupling was measured via the rates of oxygen consumption and ATP synthesis and by changes in (Δψm. Activation of mKATP partially uncoupled mitochondria 9–14% and partially depolarized (Δψm. Ca2+ fluorescence increased and NMDAR currents decreased with anoxia, mKATP activation and uniporter blockade. These changes were abolished by activation of the uniporter. mKATP blockade abolished the anoxic and mKATP mediated changes but not those mediated by the uniporter. These data show that the anoxic attenuation of the NMDARs is mediated by mitochondrial Ca2+ handling, which is in turn modulated by mKATP activity. Supported by an NSERC Grant to LTB.

Effects of cold on murine brain mitochondrial function

“…For example, reduced ETS respiratory flux and/or mild uncoupling of the proton (H + ) gradient is commonly observed in isolated mitochondria from various tissues of hypoxia-adapted species [14–17]. Beyond energetics, mitochondria are cellular signalling hubs that detect and integrate low oxygen signals, and then initiate either cell death cascades or neuroprotective strategies [18–21]. Therefore, mitochondria are at the center of both neuronal energy production in normoxia and also the cellular decision between initiating neuroprotective responses vs .…”