N-methyl-4-phenylpyridine (MMP+) Together With 6-hydroxydopamine or Dopamine Stimulates Ca2+ Release From Mitochondria

FEBS Lett. 1986 Mar 17;198(1):99-102. doi: 10.1016/0014-5793(86)81192-9.

Abstract

The nigrostriatal neurotoxin N-methyl-1,2,3,6-tetrahydropyridine (MPTP) causes Parkinsonism in humans and laboratory animals. MPTP neurotoxicity is dependent on its oxidation to N-methyl-4-phenylpyridine (MPP+). The mechanism by which MPP+ causes destruction of dopamine-containing nigrostriatal cells is unknown. Here we show that MPP+ but not MPTP is taken up by energized mitochondria. MPP+ in the presence of dopamine and particularly of 6-hydroxydopamine stimulates Ca2+ release from mitochondria. Ca2+ release is accompanied by hydrolysis of intramitochondrial pyridine nucleotides. Our findings suggest that the MPTP-induced model of Parkinson's disease may be due to a disturbed Ca2+ homeostasis in dopamine neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Calcium / metabolism*
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Dopamine / pharmacology*
  • Egtazic Acid / pharmacology
  • Female
  • Hydroxydopamines / pharmacology*
  • In Vitro Techniques
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • NAD / metabolism
  • Oxidopamine
  • Parkinson Disease, Secondary / chemically induced
  • Pyridines / metabolism
  • Pyridines / toxicity
  • Pyridinium Compounds / metabolism
  • Pyridinium Compounds / toxicity*
  • Rats
  • Rats, Inbred Strains

Substances

  • Hydroxydopamines
  • Pyridines
  • Pyridinium Compounds
  • NAD
  • Egtazic Acid
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Oxidopamine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Calcium
  • Dopamine