title: Increased potassium conductance of brain mitochondria induces resistance to permeability transition by enhancing matrix volume.
abstract: Modulation of K(+) conductance of the inner mitochondrial membrane has been proposed to mediate preconditioning in ischemia-reperfusion injury. The mechanism is not entirely understood, but it has been linked to a decreased activation of mitochondrial permeability transition (mPT). In the present study K(+) channel activity was mimicked by picomolar concentrations of valinomycin. Isolated brain mitochondria were exposed to continuous infusions of calcium. Monitoring of extramitochondrial Ca(2+) and mitochondrial respiration provided a quantitative assay for mPT sensitivity by determining calcium retention capacity (CRC). Valinomycin and cyclophilin D inhibition separately and additively increased CRC. Comparable degrees of respiratory uncoupling induced by increased K(+) or H(+) conductance had opposite effects on mPT sensitivity. Protonophores dose-dependently decreased CRC, demonstrating that so-called mild uncoupling was not beneficial per se. The putative mitoK(ATP) channel opener diazoxide did not mimic the effect of valinomycin. An alkaline matrix pH was required for mitochondria to retain calcium, but increased K(+) conductance did not result in augmented DeltapH. The beneficial effect of valinomycin on CRC was not mediated by H(2)O(2)-induced protein kinase Cepsilon activation. Rather, increased K(+) conductance reduced H(2)O(2) generation during calcium infusion. Lowering the osmolarity of the buffer induced an increase in mitochondrial volume and improved CRC similar to valinomycin without inducing uncoupling or otherwise affecting respiration. We propose that increased potassium conductance in brain mitochondria may cause a direct physiological effect on matrix volume inducing resistance to pathological calcium challenges.
authors.affiliation: Mitochondrial Pathophysiology Unit, Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden. magnus.hansson@med.lu.se
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Saori
authors.initials: S
authors.lastname: Morota
authors.forename: Maria
authors.initials: M
authors.lastname: Teilum
authors.forename: Gustav
authors.initials: G
authors.lastname: Mattiasson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D000468:Alkalies / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006859:Hydrogen / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D053142:Mitochondrial Size / Q000187:drug effects; D018716:Molecular Mimicry / Q000187:drug effects; D009550:Nigericin / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D000468:Alkalies; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D014634:Valinomycin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D006859:Hydrogen; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D003981:Diazoxide; D009550:Nigericin; D011188:Potassium; D002118:Calcium