Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury?
For S-nitrosothiols and peroxynitrite to interfere with the activity of mitochondrial complex I, prior transition of the enzyme from its active (A) to its deactive, dormant (D) state is necessary. We now demonstrate accumulation of the D-form of complex I in human epithelial kidney cells after prolonged hypoxia. Upon reoxygenation after hypoxia there was an initial delay in the return of the respiration rate to normal. This was due to the accumulation of the D-form and its slow, substrate-dependent reconversion to the A-form. Reconversion to the A-form could be prevented by prolonged incubation with endogenously generated NO. We propose that the hypoxic transition from the A-form to the D-form of complex I may be protective, because it would act to reduce the electron burst and the formation of free radicals during reoxygenation. However, this may become an early pathophysiological event when NO-dependent formation of S-nitrosothiols or peroxynitrite structurally modifies complex I in its D-form and impedes its return to the active state. These observations provide a mechanism to account for the severe cell injury that follows hypoxia and reoxygenation when accompanied by NO generation.
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT. Electronic address: a.galkin@qub.ac.uk.
Alexander
A
Galkin
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.
Andrey Y
AY
Abramov
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT.
Nanci
N
Frakich
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT.
Michel R
MR
Duchen
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT.
Salvador
S
Moncada
D000818:Animals; D002417:Cattle; D042967:Electron Transport Complex I / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology*; D006801:Humans; D007511:Ischemia / Q000201:enzymology*; D007668:Kidney / Q000098:blood supply / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D010101:Oxygen Consumption; D030421:Peroxynitrous Acid / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D042967:Electron Transport Complex I