Bioenergetic consequences of heterozygous alpha-ketoglutarate dehydrogenase complex mutation
Kokas Márton
János Szentágothai Neurosciences Division
Dr. Bereczki Dániel
SE Neurológiai és Pszichiátriai Klinika közös tanterme
2026-10-19 15:00:00
Functional neurosciences
Dr. Sperlágh Beáta
Dr. Tretter László és Dr. Komlódi Tímea
Dr. Konrád Csaba
Dr. Radnai Balázs
Dr. Buzás Edit
Dr. Tanka-Salamon Anna
Dr. Bay Péter
In this work, we have examined DLST+/--DLD+/- double heterozygous KO mice under in vitro and in vivo conditions. KGDHc is commonly known as a key enzyme of the TCAc and therefore of mitochondrial energy production. On one hand, the enzyme complex produces NADH for OXPHOS and succinyl-CoA for SLP. On the other hand, it generates a significant amount of ROS under a high NADH/NAD+ ratio. The malfunction of KGDHc is related to many neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
Earlier models with genetic modification of the E1k, E2k, or E3 subunit could not identify any alteration in the phenotype, unless an additional toxin or inhibitor was administered. In this study, we aimed to examine the effect of double heterozygous KO of DLST and DLD. Of note, this genetic modification had previously been generated by another laboratory, however, have published only in vitro mitochondrial results.
Our in vitro experiments showed that both the O2 consumption and the ATP synthesis rate were decreased in DKO animals compared to WT in a substrate-specific manner. However, ROS production was also decreased in the mutant groups at a high NADH/NAD+ ratio. In line with that, higher aconitase activity was detected in mutants after incubation with a high concentration of Succ. In the in vivo experiments, there were no significant alterations were detected in activity, food and oxygen consumption, or blood amino acid and acylcarnitine profiles. Nevertheless, DKO mice showed decreased performance in the treadmill fatigue-endurance test compared to controls and the cognitive performance of older DKO rodents was reduced. Immunohistology experiments revealed that cortices of older DKO mice suffer from microgliosis and neuronal death was observed in the CA1 subfield of the hippocampus. Additional immunostaining showed that DKO brain mitochondria are fragmented and express lower levels of PGC-1α and Nrf2.
In conclusion, we can state that under resting, physiological circumstances, DKO mice can compensate well. Nonetheless, under high energy demand conditions, DKO mice cannot adequately compensate for the reduced expression of this crucial mitochondrial enzyme.
