PhD Scientific Days 2024

Poster Session A - Molecular Medicine 1.

Significant mitochondrial malfuntions in KGDH double-heterozygous KO mice are associated with minor behavioural and metabolic abnormalities but decreased tolerance to forced movement

Előadó neve

Dr. Kokas, Márton

Neptun code

AN0KPL

Előadó munkahelye

Department of Biochemistry, Semmelweis University

Előadó telefonszáma

06202786924

Előadó e-mail címe

kokas.marton@semmelweis.hu

Az előadás címe

Significant mitochondrial malfuntions in KGDH double-heterozygous KO mice are associated with minor behavioural and metabolic abnormalities but decreased tolerance to forced movement

Szerző(k) neve és munkahelye

Márton Kokas¹

1: Semmelweis Egyetem Orvosi Biokémiai Intézet

Bemutatás módja

Poszter

Szekció

Poster Session A - Molecular Medicine 1.

Language of the presentation

English

Preferred session

Molecular Medicine

Összefoglaló szövege

Introduction: α-ketoglutarate dehydrogenase complex (αKGDHc, or oxoglutarate dehydrogenase complex) is the rate limiting enzyme in the tricarboxylic acid (TCA) cycle catalysing the oxidative decarboxilation of the α-ketoglutarate, while producing NADH for oxidative phosphorylation and succinyl-CoA for the substrate level phosphorylation (SLP); thus, being a crucial point in the mitochondrial ATP production. Additionally, αKGDHc is a major producer of reactive oxygen species (ROS). The complex is built up by three types of subunits: α-KGDH (E1), dihydrolipoyl succinyltransferase (E2), and dihydrolipoyl dehydrogenase (E3).
Aims: E2 and E3 heterozygous knock-out (DKO) male middle-aged (200-250 day old) mice have been used to examine the in vitro and in vivo effects of this mutation. Of note, homozygous KO mice die in utero emphasizing the important role of αKGDHc in oxidative metabolism.
Methods: The mRNA levels of mitochondrial enzymes were determined from liver samples. Histological studies were carried out on skeletal muscle samples. Mitochondria isolated from brain and kidneys were used to measure mitochondrial ATP production, oxygen consumption, ROS generation and aconitase activity. In vivo experiments included metabolic experiments in metabolic cage, behavioural tests and endurance test.
Result: Our in vitro results show that in DKO animals both oxygen consumption and ATP production were decreased with α-ketoglutarate as substrate compared to the WT animals. DKO mice produced less ROS during succinate-induced reverse electron transfer (RET). In line with that, higher aconitase activity was measured in DKO brain mitochondria. In the in vivo metabolic experiments, there were some trends and also in the behavioural tests, small differences were detectable between the two groups indicating a minor metabolic and cognitive decline. Importantly, DKO animals showed a decreased performance in the trademill fatigue test, which could not be explained by fibrotic alterations in the skeletal muscle.
Conclusion: Taken together, these data show that heterozygous DKO mice have significant in vitro changes compared to the WT animals, which is not reflected in significant differences in the phenotype. This is the first study analysing the phenotype of the αKGDHc DKO mice.
Funding: EFOP-3.6.3-VEKOP-16-2017-00009

University

Semmelweis University

Supervisor

Prof. László Tretter DSc.

Publication of my abstract

I give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6865

Start

15:20

End

15:23