The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism

The mitochondrial transition pore (MTP) is implicated as a mediator of cell injury and death in many situations. The MTP opens in response to stimuli including reactive oxygen species and inhibition of the electron transport chain. Sporadic Parkinson's disease (PD) is characterized by oxidative stre ss and specifically involves a defect in complex I of the electron transpor t chain. To explore the possible involvement of the MTP in PD models, we te sted the effects of the complex I inhibitor and apoptosis-inducing toxin N- methyl-4-phenylpyridinium (MPP+) on cyclosporin A (CsA)-sensitive mitochond rial swelling and release of cytochrome c. In the presence of Ca2+ and P-i, MPP+ induced a permeability transition in both liver and brain mitochondri a. MPP+ also caused release of cytochrome c from liver mitochondria. Roteno ne, a classic non-competitive complex I inhibitor, completely inhibited MPP +-induced swelling and release of cytochrome c. The MPP+-induced permeabili ty transition was synergistic with nitric oxide and the adenine nucleotide translocator inhibitor atractyloside, and additive with phenyl arsine oxide cross-linking of dithiol residues. MPP+-induced pore opening and cytochrom e c release were blocked by CsA, the Ca2+ uniporter inhibitor ruthenium red , the hydrophobic disulfide reagent N-ethylmaleimide, butacaine, and the fr ee radical scavenging enzymes catalase and superoxide dismutase. MPP+ neuro toxicity may derive from not only its inhibition of complex I and consequen t ATP depletion, but also from its ability to open the MTP and to release m itochondrial factors including Ca2+ and cytochrome c known to be involved i n apoptosis. (C) 1999 Elsevier Science B.V. All rights reserved.