PhD Scientific Days 2026

Poster Session 2.M - Neurosciences

Cognitive decline, microgliosis and mitochondrial dysfunction of α-ketoglutarate dehydrogenase double heterozygous knockout mice

Name of the presenter

Kokas, Márton

Institute/workplace of the presenter

Department of Biochemistry

Authors

Márton Kokas¹, Tímea Komlódi¹, András Budai², Tímea Téglás³, Lei Zhou³, László Tretter¹
1: Department of Biochemistry
2: Department of Pathology, Forensic and Insurance Medicine
3: Hungarian University of Sports Sciences

Text of the abstract

α-ketoglutarate dehydrogenase complex (αKGDHc) catalyzes the oxidative decarboxylation of αKG in the tricarboxylic acid cycle, producing NADH for oxidative phosphorylation and succinyl-CoA for substrate level phosphorylation. αKGDHc is built up by three types of subunits: α-ketoglutarate dehydrogenase (E1k), dihydrolipoyl succinyltransferase (E2k), and dihydrolipoyl dehydrogenase (E3), which is the common subunit of α-keto acid dehydrogenases including pyruvate dehydrogenase complex. Earlier studies of our group demonstrated that E1k-E2k and E3 subcomplexes can generate a sizeable amount of reactive oxygen species (ROS) under pathological conditions, such as acidosis (E1k-E2k) and high NADH/NAD+ ratio (E3). Other groups also published that dysfunction of αKGDHc may play a role in neurodegenerative diseases.
In the current study we used E2k and E3 double heterozygous knockout (DKO) C57Bl/6 middle aged male mice to characterize the in vitro and in vivo changes in the brain compared to wild type (WT) animals. Of note, Homozygous knockout of these respective genes results in utero death. The mRNA levels of mitochondrial and cytosolic enzymes were determined from liver samples. Mitochondria isolated from brain were used to measure mitochondrial ATP production, oxygen consumption, and ROS generation. In vivo experiments included behavioural tests like open field- and Morris water maze tests. Histological studies were carried out on cerebral cortex and on hypophysis.
In vitro O2 consumption and ATP production were decreased in knock out rodents when mitochondria were energized with αKG. Nevertheless, ROS production was also reduced in substrate-specific manners. In vivo DKO mice showed minor cognitive decline in behavioral tests accompanied by cortical microgliosis and neuronal death in the Cornu Ammonis. Moreover, histological results exhibited increased levels of dynamin-related protein 1 and lower levels of mitofusin 2, peroxisome proliferator-activated receptor gamma coactivator 1-alpha.
This study proved that DKO mice bear several malfunctions in vitro, but no phenotypical alterations were found under resting conditions. However, when animals were subjected to stress situation, compensatory mechanisms were insufficient. Thus animals exhibited stress-related responses, ultimately leading to long-term microgliosis.
Funding: SE Predoctoral Scholarship