Molecular mechanism and physiological role of active-deactive transition of mitochondrial complex I.
The unique feature of mitochondrial complex I is the so-called A/D transition (active-deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min-1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1-10 min-1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.
*Queen's University Belfast, School of Biological Sciences, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, U.K.
Marion
M
Babot
Alexander
A
Galkin
D002384:Catalysis; D015687:Cell Hypoxia / Q000502:physiology; D042967:Electron Transport Complex I / Q000737:chemistry / Q000378:metabolism*; D004734:Energy Metabolism; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000737:chemistry / Q000378:metabolism*
D017382:Reactive Oxygen Species; D009243:NAD; D014451:Ubiquinone; D009569:Nitric Oxide; D042967:Electron Transport Complex I; D010100:Oxygen