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Nitric oxide enhances MPP(+) inhibition of complex I

M W Cleeter1, J M Cooper, A H Schapira

  • 1University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK.

FEBS Letters
|August 28, 2001
PubMed

Insights

Nitric oxide (NO(*-)) may worsen the effects of 1-methyl-4-phenylpyridinium (MPP(+)) on mitochondrial complex I. This interaction primes the respiratory chain, potentially explaining MPP(+) toxicity.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Toxicology

Background:

  • 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) toxicity involves mitochondrial complex I inhibition and free radical generation.
  • 7-Nitroindazole, a nitric oxide (NO(*-)) synthase inhibitor, offers protection against MPTP toxicity.

Purpose of the Study:

  • To investigate the interaction between nitric oxide (NO(*-)) and 1-methyl-4-phenylpyridinium (MPP(+)) in the context of mitochondrial respiration.
  • To elucidate the role of NO(*-) in potentiating MPP(+)-induced mitochondrial dysfunction.

Main Methods:

  • Utilized brain submitochondrial particles to assess mitochondrial complex I activity.
  • Examined the effects of a NO(*-) generator (glutathione-N-oxide) on MPP(+)-induced inhibition of complex I.
  • Investigated the impact of NO(*-) on complex IV (cytochrome oxidase) activity.

Main Results:

  • Glutathione-N-oxide enhanced the inhibitory effect of MPP(+) on mitochondrial complex I activity.
  • NO(*-) induced a reversible inhibition of complex IV (cytochrome oxidase).
  • MPP(+) caused an irreversible, free radical-mediated inhibition of complex I.

Conclusions:

  • NO(*-) potentiates MPP(+)-induced complex I inhibition, likely by reversibly inhibiting complex IV.
  • This NO(*-)-mediated effect primes the respiratory chain, making it more susceptible to MPP(+).
  • An interaction between NO(*-) and MPP(+) occurs at the mitochondrial respiratory chain level, contributing to neurotoxicity.

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