The mitochondrial permeability transition pore and its role in anaesthesia-triggered cellular protection during ischaemia-reperfusion injury.
This review summarises the most recent data in support of the role of the mitochondrial permeability transition pore (mPTP) in ischaemia-reperfusion injury, how anaesthetic agents interact with this molecular channel, and the relevance this holds for current anaesthetic practice. Ischaemia results in damage to the electron transport chain of enzymes and sets into play the assembly of a non-specific mega-channel (the mPTP) that transgresses the inner mitochondrial membrane. During reperfusion, uncontrolled opening of the mPTP causes widespread depolarisation of the inner mitochondrial membrane, hydrolysis of ATP, mitochondrial rupture and eventual necrotic cell death. Similarly, transient opening of the mPTP during less substantial ischaemia leads to differential swelling of the intermembrane space compared to the mitochondrial matrix, rupture of the outer mitochondrial membrane and release of pro-apoptotic factors into the cytosol. Recent data suggests that cellular protection from volatile anaesthetic agents follows specific downstream interactions with this molecular channel that are initiated early during anaesthesia. Intravenous anaesthetic agents also prevent the opening of the mPTP during reperfusion. Although by dissimilar mechanisms, both volatiles and propofol promote cell survival by preventing uncontrolled opening of the mPTP after ischaemia. It is now considered that anaesthetic-induced closure of the mPTP is the underlying effector mechanism that is responsible for the cytoprotection previously demonstrated in clinical studies investigating anaesthetic-mediated cardiac and neuroprotection. Manipulation of mPTP function offers a novel means of preventing ischaemic cell injury. Anaesthetic agents occupy a unique niche in the pharmacological armamentarium available for use in preventing cell death following ischaemia-reperfusion injury.
Department of Anaesthesia, Mater Misericordiae Health Services, Brisbane, Queensland, Australia. David.Andrews@heartweb.com
David T
DT
Andrews
Colin
C
Royse
Alistair G
AG
Royse
D000255:Adenosine Triphosphate / Q000378:metabolism; D000758:Anesthesia / Q000379:methods; D000777:Anesthetics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015427:Reperfusion Injury / Q000503:physiopathology*
D000777:Anesthetics; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000255:Adenosine Triphosphate