Complex I is the major site of mitochondrial superoxide production by paraquat.

TitleComplex I is the major site of mitochondrial superoxide production by paraquat.
Publication TypeJournal Article
Year of Publication2008
AuthorsCochemé, HM, Murphy, MP
JournalJ Biol Chem
Volume283
Issue4
Pagination1786-98
Date Published2008 Jan 25
ISSN0021-9258
KeywordsAnimals, DNA Damage, Electron Transport Complex I, Herbicides, Membrane Potential, Mitochondrial, Mitochondria, Heart, Mitochondria, Liver, Oxidative Stress, Paraquat, Rats, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Species Specificity, Superoxide Dismutase, Superoxides
Abstract

Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride) is widely used as a redox cycler to stimulate superoxide production in organisms, cells, and mitochondria. This superoxide production causes extensive mitochondrial oxidative damage, however, there is considerable uncertainty over the mitochondrial sites of paraquat reduction and superoxide formation. Here we show that in yeast and mammalian mitochondria, superoxide production by paraquat occurs in the mitochondrial matrix, as inferred from manganese superoxide dismutase-sensitive mitochondrial DNA damage, as well as from superoxide assays in isolated mitochondria, which were unaffected by exogenous superoxide dismutase. This paraquat-induced superoxide production in the mitochondrial matrix required a membrane potential that was essential for paraquat uptake into mitochondria. This uptake was of the paraquat dication, not the radical monocation, and was carrier-mediated. Experiments with disrupted mitochondria showed that once in the matrix paraquat was principally reduced by complex I (mammals) or by NADPH dehydrogenases (yeast) to form the paraquat radical cation that then reacted with oxygen to form superoxide. Together this membrane potential-dependent uptake across the mitochondrial inner membrane and the subsequent rapid reduction to the paraquat radical cation explain the toxicity of paraquat to mitochondria.

DOI10.1074/jbc.M708597200
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M708597200
PubMed ID18039652
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom