title: Permeability transition in rat liver mitochondria is modulated by the ATP-Mg/Pi carrier.
abstract: Mitochondrial permeability transition, due to opening of the permeability transition pore (PTP), is triggered by Ca2+ in conjunction with an inducing agent such as phosphate. However, incubation of rat liver mitochondria in the presence of low micromolar concentrations of Ca2+ and millimolar concentrations of phosphate is known to also cause net efflux of matrix adenine nucleotides via the ATP-Mg/Pi carrier. This raises the possibility that adenine nucleotide depletion through this mechanism contributes to mitochondrial permeability transition. Results of this study show that phosphate-induced opening of the mitochondrial PTP is, at least in part, secondary to depletion of the intramitochondrial adenine nucleotide content via the ATP-Mg/Pi carrier. Delaying net adenine nucleotide efflux from mitochondria also delays the onset of phosphate-induced PTP opening. Moreover, mitochondria that are depleted of matrix adenine nucleotides via the ATP-Mg/Pi carrier show highly increased susceptibility to swelling induced by high Ca2+ concentration, atractyloside, and the prooxidant tert-butylhydroperoxide. Thus the ATPMg/Pi carrier, by regulating the matrix adenine nucleotide content, can modulate the sensitivity of rat liver mitochondria to undergo permeability transition. This has important implications for hepatocytes under cellular conditions in which the intramitochondrial adenine nucleotide pool size is depleted, such as in hypoxia or ischemia, or during reperfusion when the mitochondria are exposed to increased oxidative stress.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, United Kingdom.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lagace
authors.forename: Josephine S
authors.initials: JS
authors.lastname: Modica-Napolitano
authors.forename: June R
authors.initials: JR
authors.lastname: Aprille
mesh_terms: D000244:Adenosine Diphosphate / Q000032:analysis; D000249:Adenosine Monophosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000502:physiology*; D001278:Atractyloside / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D004533:Egtazic Acid / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism; D008930:Mitochondria, Liver / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D024101:Mitochondrial Proteins; D008933:Mitochondrial Swelling / Q000187:drug effects; D009840:Oligomycins / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D024101:Mitochondrial Proteins; D009840:Oligomycins; D010710:Phosphates; D001278:Atractyloside; D000249:Adenosine Monophosphate; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D008274:Magnesium; D002118:Calcium