Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion

Abstract

1. The yield of mitochondria isolated from perfused hearts subjected to 30 min ischaemia followed by 15 min reperfusion was significantly less than that for control hearts, and this was associated with a decrease in the rates of ADP-stimulated respiration. 2. The presence of 0.2 microM cyclosporin A (CsA) in the perfusion medium during ischaemia and reperfusion caused mitochondrial recovery to return to control values, but did not reverse the inhibition of respiration. 3. A technique has been devised to investigate whether the Ca(2+)-induced non-specific pore of the mitochondrial inner membrane opens during ischaemia and/or reperfusion of the isolated rat heart. The protocol involved loading the heart with 2-deoxy[3H]glucose ([3H]DOG), which will only enter mitochondria when the pore opens. Subsequent isolation of mitochondria demonstrated that [3H]DOG did not enter mitochondria during global isothermic ischaemia, but did enter during the reperfusion period. 4. The amount of [3H]DOG that entered mitochondria increased with the time of ischaemia, and reached a maximal value after 30-40 min of ischaemia. 5. CsA at 0.2 microM did not prevent [3H]DOG becoming associated with the mitochondria, but rather increased it; this was despite CsA having a protective effect on heart function similar to that shown previously [Griffiths and Halestrap (1993) J. Mol. Cell. Cardiol. 25, 1461-1469]. 6. The non-immunosuppressive CsA analogue [MeAla6]cyclosporin was shown to have a similar Ki to CsA on purified mitochondrial peptidyl-prolyl cis-trans-isomerase and mitochondrial pore opening, and also to have a similar protective effect against reperfusion injury. 7. Using isolated heart mitochondria, it was demonstrated that pore opening could become CsA-insensitive under conditions of adenine nucleotide depletion and high matrix [Ca2+] such as may occur during the initial phase of reperfusion. The apparent increase in mitochondrial [3H]DOG in the CsA-perfused hearts is explained by the ability of the drug to stabilize pore closure and so decrease the loss of [3H]DOG from the mitochondria during their preparation.

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…The link between respiratory inhibition, slow electron re-introduction, and cardioprotection is elusive, but likely involves inhibition of pathologic events such as mitochondrial Ca 2+ overload, ROS generation and PT pore opening, which occur at the end of ischemia/onset of reperfusion [1,70,71]. Although the effects of SNO-mediated complex I inhibition on Δ ψm were not determined, it is to be expected that complex I inhibition would decrease Δ ψm , which would inhibit Ca 2+ overload and ROS generation.…”

Regulation of cardiovascular cell function by hydrogen sulfide (H2S)

“…53 There is also a restoration of normal pH. 53 (1), cytosolic/mitochondrial Ca 2þ overload (2), and mitochondrial permeability transition pore (mPTP) opening (3). Recent evidence supports the notion that protective interventions such as preconditioning, postconditioning and autacoids such as adenosine, bradykinin and opioid peptides (4) are able to attenuate injurious Ca 2þ overload and mPTP opening by activating counter-regulatory survival signalling pathways during reperfusion.…”

“…53 During the initial stages of reperfusion there is an increase in the production of ROS and mitochondrial Ca 2þ . 53 There is also a restoration of normal pH. 53 (1), cytosolic/mitochondrial Ca 2þ overload (2), and mitochondrial permeability transition pore (mPTP) opening (3).…”

Comment utiliser le paradigme de préconditionnement ischémique pour protéger le myocarde ?

“…E.J. Griffiths et al ont montré il y a plusieurs années que le pore de transition de perméabilité, dont le rôle est déterminant dans le passage des lésions cellulaires d'un stade réversible à un stade irréversible, ne s'ouvre pas lors de l'ischémie, mais lors de la reperfusion [31]. Corroborant cette donnée et en accord avec le concept de postconditionnement, nous avons récemment montré, avec d'autres, que le blocage du pore de transition de perméabilité par l'administration de ciclosporine A juste au moment de la reperfusion a un effet protecteur comparable à celui du préconditionnement [32].…”