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dc.contributor.author Ravasz Dóra
dc.contributor.author Kacsó Gergely
dc.contributor.author Fodor Viktória
dc.contributor.author Horváth Kata
dc.contributor.author Ádám Veronika
dc.contributor.author Chinopoulos Christos
dc.date.accessioned 2018-10-10T07:08:54Z
dc.date.available 2018-10-10T07:08:54Z
dc.date.issued 2017
dc.identifier 85015426540
dc.identifier.citation pagination=41-53; journalVolume=109; journalTitle=NEUROCHEMISTRY INTERNATIONAL;
dc.identifier.uri http://repo.lib.semmelweis.hu//handle/123456789/5089
dc.identifier.uri doi:10.1016/j.neuint.2017.03.008
dc.description.abstract GABA is catabolized in the mitochondrial matrix through the GABA shunt, encompassing transamination to succinic semialdehyde followed by oxidation to succinate by the concerted actions of GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), respectively. Gamma-hydroxybutyrate (GHB) is a neurotransmitter and a psychoactive drug that could enter the citric acid cycle through transhydrogenation with alpha-ketoglutarate to succinic semialdehyde and d-hydroxyglutarate, a reaction catalyzed by hydroxyacid-oxoacid transhydrogenase (HOT). Here, we tested the hypothesis that the elevation in matrix succinate concentration caused by exogenous addition of GABA, succinic semialdehyde or GHB shifts the equilibrium of the reversible reaction catalyzed by succinate-CoA ligase towards ATP (or GTP) hydrolysis, effectively negating substrate-level phosphorylation (SLP). Mitochondrial SLP was addressed by interrogating the directionality of the adenine nucleotide translocase during anoxia in isolated mouse brain and liver mitochondria. GABA eliminated SLP, and this was rescued by the GABA-T inhibitors vigabatrin and aminooxyacetic acid. Succinic semialdehyde was an extremely efficient substrate energizing mitochondria during normoxia but mimicked GABA in abolishing SLP in anoxia, in a manner refractory to vigabatrin and aminooxyacetic acid. GHB could moderately energize liver but not brain mitochondria consistent with the scarcity of HOT expression in the latter. In line with these results, GHB abolished SLP in liver but not brain mitochondria during anoxia and this was unaffected by either vigabatrin or aminooxyacetic acid. It is concluded that when mitochondria catabolize GABA or succinic semialdehyde or GHB through the GABA shunt, their ability to perform SLP is impaired.
dc.relation.ispartof urn:issn:0197-0186
dc.title Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation.
dc.type Journal Article
dc.date.updated 2018-03-09T10:00:23Z
dc.language.rfc3066 en
dc.identifier.mtmt 3204237
dc.identifier.pubmed 28300620


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