title: Thapsigargin directly induces the mitochondrial permeability transition.
abstract: High concentrations of thapsigargin (TG) have been used to study the process of necrotic cell death, which involves mitochondria in the cell rapidly undergoing the mitochondrial permeability transition (MPT). We therefore investigated the effects of TG on MPT in isolated liver and heart mitochondria. Using a matrix swelling assay in combination with a novel enzymatic method based on inner membrane permeability to citrate synthase substrates, TG induced MPT in a concentration-dependent manner, independent of extramitochondrial [Ca2+] and inhibitable by cyclosporin A. Evidence from alamethicin-permeabilized mitochondria suggests that TG induces MPT by causing Ca2+ release from mitochondrial matrix Ca2+-binding sites. These findings suggest that the MPT-inducing effect of TG may contribute to its pro-necrotic and pro-apoptotic effects in various cell types.
authors.affiliation: The UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA School of Medicine, Los Angeles, CA 90095-1760, USA.
authors.forename: P
authors.initials: P
authors.lastname: Korge
authors.forename: J N
authors.initials: JN
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D003524:Cyclosporins / Q000378:metabolism*; D007473:Ion Channels; D008929:Mitochondria, Heart / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D019284:Thapsigargin / Q000494:pharmacology*
chemical_list: D003524:Cyclosporins; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019284:Thapsigargin; D002118:Calcium