Redox properties of the adenoside triphosphate‐sensitive K⁺ channel in brain mitochondria

Abstract

Brain mitochondrial ATP-sensitive K+ channel (mitoK(ATP)) opening by diazoxide protects against ischemic damage and excitotoxic cell death. Here we studied the redox properties of brain mitoK(ATP) . MitoK(ATP) activation during excitotoxicity in cultured cerebellar granule neurons prevented the accumulation of reactive oxygen species (ROS) and cell death. Furthermore, mitoK(ATP) activation in isolated brain mitochondria significantly prevented H2O2 release by these organelles but did not change Ca2+ accumulation capacity. Interestingly, the activity of mitoK(ATP) was highly dependent on redox state. The thiol reductant mercaptopropionylglycine prevented mitoK(ATP) activity, whereas exogenous ROS activated the channel. In addition, the use of mitochondrial substrates that led to higher levels of endogenous mitochondrial ROS release closely correlated with enhanced K+ transport activity through mitoK(ATP). Altogether, our results indicate that brain mitoK(ATP) is a redox-sensitive channel that controls mitochondrial ROS release.

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…This is consistent with recent studies that suggest cross-talk signaling between both the cytosolic NADPH oxidase and mitochondria in several types of cells, and that mitoK(ATP) play a major role in this interaction (Brandes 2005;Daiber 2010;Dikalova et al 2010;Doughan et al 2008). Therefore, NADPH oxidase may lead to mitoK(ATP) channel opening, which play a major role in modulating intracellular ROS (Andrukhiv et al 2006;Costa and Garlid 2008;Mattson and Liu 2003) via regulation of the formation/release of ROS from the mitochondria, and integration of signals from diverse sources (Facundo et al 2007;Fornazari et al 2008;Oldenburg et al 2002). ROS open up mitoK(ATP), and mitochondrial ROS production can be stimulated by the opening of mitochondrial mitoK(ATP) channels (Costa and Garlid 2008;Kimura et al 2005b;Zhang et al 2002).…”

“…Brain mitochondria contain seven times more mitoK(ATP) channels per milligram of mitochondrial protein than liver or heart (Bajgar et al 2001;Bednarczyk 2009). It is therefore possible that, as suggested for peripheral tissues (Facundo et al 2007;Fornazari et al 2008;Oldenburg et al 2002), these channels provide in dopaminergic neurons a convergent target that could integrate ROS induced by low levels of neurotoxins (6-OHDA or MPP + ) with angiotensin/NADPH oxidase-induced ROS to increase dopaminergic neuron oxidative stress and cell death. It may be speculated that low doses of neurotoxins, or other factors in PD, may generate low levels of ROS by several mechanisms that are insufficient to induce dopaminergic cell death.…”

Mitochondrial Pathways, Permeability Transition Pore, and Redox Signaling in Cardioprotection: Therapeutic Implications

“…Pharmacological opening of mK ATP channels by diazoxide contributes to the formation of small amounts of ROS inducing cardioprotection (74,109,129,142,143). Also NO donors can activate mK ATP channels in rabbit ventricular myocytes and can potentiate the protective effect of the mK ATP channel opener diazoxide (310 (102,110,292,389). The latter two species also inhibit mitochondrial complex II.…”

“…Indeed, even under physiological conditions, a minor fraction of oxygen ( < 0.1%) is transformed into O 2 -at the level of complexes I and III; SOD then rapidly converts O 2 -to H 2 O 2 that is freely diffusible through membranes (110). The production of H 2 O 2 can increase during myocardial challenging, such as during increased cardiac work load (307 or Cu 2 + , represents a dangerous step, because an increase in toxicity can occur.…”

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

“…It is known that the NADPH oxidase complex is the most important intracellular source of ROS apart from mitochondria (Babior, 1999(Babior, , 2004Seshiah et al, 2002;Cai et al, 2003) and that it generates and releases ROS in short oxidative bursts for signaling functions (Bokoch and Knaus, 2003;Ritsick et al, 2004;Leto et al, 2009). In addition, several studies support a critical role for mitochondrial ATP-sensitive potassium channels (mitoKATP) in modulating intracellular ROS (Mattson and Liu, 2003;Costa and Garlid, 2008) by means of regulation of the formation/ release of ROS from the mitochondria, and integration of signals from diverse sources Facundo et al, 2007;Fornazari et al, 2008). ROS open up KATP channels (Zhang et al, 2002;Avshalumov and Rice, 2003), and mitochondrial ROS production can be stimulated by the opening of mitochondrial mitoKATP channels (Costa and Garlid, 2008;Kimura et al, 2005b).…”