title: The inhibitors of antioxidant cell enzymes induce permeability transition in yeast mitochondria.
abstract: In this study we investigated the effects of exogenous and endogenous oxidative stress on mitochondrial membrane permeability transition in yeast cells. E. magnusii yeast was used in the study as it is the only yeast strain possessing a natural high-capacity Са²⁺ transport system. The key reactive oxygen species (ROS) detoxifying enzymes in the yeast cells--catalases (CATs) and superoxide dismutases (SODs)--were fully characterized. At least five isoforms of SODs and only one isoform of CATs were found in the E. magnusii mitochondria. The assessment of the main properties of mitochondrial non-specific permeability under physiological conditions such as dynamics of the membrane potential (∆Ψ) and swelling in mitochondria showed that under physiological conditions classical inhibitors of CATs (ATZ--3-amino-1, 2, 4-triazole) and of SODs (DDC--diethyldithiocarbamate) caused irreversible decline in ∆Ψ in the yeast mitochondria. This decline was accelerated in the presence of 500 μM Са²⁺. The combined action of the inhibitors (ATZ + DDC) promoted moderate swelling in the isotonic medium, which was confirmed by transmission electron microscopy. Mitochondrial swelling in the cells exposed to antioxidant system inhibitors was accompanied by typical signs of early apoptosis, namely by chromatin margination and condensation, vacuolization of the cytosol, and damage of the plasma membrane. Here we showed, at both cellular and mitochondrial levels, that the deregulation of oxidant-scavenging enzymes directly leads to the opening of the mPTP, followed by induction of apoptotic markers in the whole yeast cells. Our studies are the first to clarify the highly contradictory data in the literature on mPTP in yeast mitochondria.
authors.affiliation: A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, 119071, Leninsky pr. 33, Moscow, Russia, yul_der@mail.ru.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Deryabina
authors.forename: Elena
authors.initials: E
authors.lastname: Isakova
authors.forename: Alexey
authors.initials: A
authors.lastname: Antipov
authors.forename: Nils-Erik L
authors.initials: NE
authors.lastname: Saris
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D055159:Endomyces / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D002118:Calcium