PhD Scientific Days 2017

Oral Presentations: Basic Sciences II.

Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation

Előadó neve

Ravasz, Dora

Előadó munkahelye

Semmelweis University, Department of Medical Biochemistry

Előadó telefonszáma

+36-20-6660019

Előadó e-mail címe

ravasz.dora@med.semmelweis-univ.hu

Az előadás címe

Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation

Szerző(k) neve és munkahelye

Dora Ravasz1,2, Gergely Kacso1,2, Viktoria Fodor1,2, Kata Horvath1,2, Vera Adam-Vizi1,3 and Christos Chinopoulos1,2

1 Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
2 MTA-SE Lendület Neurobiochemistry Research Group
3 MTA-SE Laboratory for Neurobiochemistry

Témacsoport

molecular sciences

Szekció

Oral Presentations: Basic Sciences II.

Data of the presenter

János Szentágothai Doctoral School of Neurosciences
Functional Neurosciences Program
Supervisor: Christos Chinopoulos
E-mail address: ravasz.dora@med.semmelweis-univ.hu

Text of the abstract

INTRODUCTON: 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 4-aminobutyrate aminotransferase (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).
AIM: 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).
METHOD: Mitochondrial SLP was addressed by interrogating the directionality of the adenine nucleotide translocase during anoxia in isolated mouse brain and liver mitochondria.
RESULTS: 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 also abolished mitochondrial SLP during anoxia and this was unaffected by GABA-T inhibitors. The effect of GHB was readily demonstrated in liver but not brain mitochondria, consistent with the scarcity of HOT expression in the latter.
CONCLUSION: It is concluded that when mitochondria catabolize GABA or succinic semialdehyde or GHB through the GABA shunt, their ability to perform SLP is impaired.

Kind

Szabad

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

1169

Authors (legacy)

Dora Ravasz1,2, Gergely Kacso1,2, Viktoria Fodor1,2, Kata Horvath1,2, Vera Adam-Vizi1,3 and Christos Chinopoulos1,2

1 Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
2 MTA-SE Lendület Neurobiochemistry Research Group
3 MTA-SE Laboratory for Neurobiochemistry