title: Identifying Compounds that Induce Opening of the Mitochondrial Permeability Transition Pore in Isolated Rat Liver Mitochondria.
abstract: The mitochondrial permeability transition pore (MPTP) is a protein pore that forms in the inner mitochondrial membrane and allows the membrane to be permeable to all molecules of less than 1500 Da. Ca(2+), numerous reactive chemicals, and oxidative stress induce MPTP opening, whereas cyclosporin A (CsA) or bongkrekic acid block it. In addition, several drugs have been shown to induce MPTP opening, leading to the loss of mitochondrial membrane potential, swelling of the matrix because of water accumulation, rupture of the outer mitochondrial membrane, and release of intermembrane space proteins into the cytosol. This ultimately leads to the rupture of the outer mitochondrial membrane and cell demise. Here, we describe an assay using isolated rat liver mitochondria that can detect Ca(2+)-dependent drug-induced opening of the MPTP, providing protocols for screening in both cuvette and 96-well format.
authors.affiliation: Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Inc, Groton, Connecticut.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marroquin
authors.forename: Rachel
authors.initials: R
authors.lastname: Swiss
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
mesh_terms: D000818:Animals; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore
keywords: mitochondria permeability transition pore; mitochondrial swelling; mitochondrial toxicity