Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice
Márton Kokas,
András Budai,
Andrea Kádár,
Soroosh Mozaffaritabar,
Lei Zhou,
Tímea Téglás,
Rebeka Sára Orova,
Dániel Gáspár,
Kristóf Németh,
Daniel Marton Toth,
Nabil V. Sayour,
Csenger Kovácsházi,
Andrea Xue,
Réka Zsuzsanna Szatmári,
Beáta Törőcsik,
Domokos Máthé,
Noémi Kovács,
Krisztián Szigeti,
Péter Nagy,
Ildikó Szatmári,
Csaba Fekete,
Tamás Arányi,
Zoltán V. Varga,
Péter Ferdinandy,
Zsolt Radák,
Andrey V. Kozlov,
László Tretter,
Tímea Komlódi,
Attila Ambrus
Affiliations
Márton Kokas
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
András Budai
Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 93 Ulloi Street, Budapest, 1091, Hungary
Andrea Kádár
Laboratory for Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, 43 Szigony Street, Budapest, 1083, Hungary
Soroosh Mozaffaritabar
Research Center for Molecular Exercise Science, Hungarian University of Sport Sciences, 44-48 Alkotas Street, Budapest, 1123, Hungary
Lei Zhou
Research Center for Molecular Exercise Science, Hungarian University of Sport Sciences, 44-48 Alkotas Street, Budapest, 1123, Hungary
Tímea Téglás
Research Center for Molecular Exercise Science, Hungarian University of Sport Sciences, 44-48 Alkotas Street, Budapest, 1123, Hungary
Rebeka Sára Orova
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
Dániel Gáspár
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
Kristóf Németh
Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 93 Ulloi Street, Budapest, 1091, Hungary
Daniel Marton Toth
Department of Molecular Biology, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
Nabil V. Sayour
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; Center for Pharmacology, Drug Research and Development, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary
Csenger Kovácsházi
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; Center for Pharmacology, Drug Research and Development, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary
Andrea Xue
Pediatric Centre, MTA Centre of Excellence, Semmelweis University, 53-54 Bokay Janos Street, Budapest, 1083, Hungary
Réka Zsuzsanna Szatmári
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, 7-9 Rath Gyorgy Street, Budapest, 1122, Hungary; Laki Kálmán Doctoral School, University of Debrecen, 98 Nagyerdei Boulevard, Debrecen, 4032, Hungary
Beáta Törőcsik
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
Domokos Máthé
Department of Biophysics and Radiation Biology, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary; Hungarian Centre of Excellence for Molecular Medicine, 9 Budapesti Street, Szeged, 6728, Hungary
Noémi Kovács
Department of Biophysics and Radiation Biology, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary; Hungarian Centre of Excellence for Molecular Medicine, 9 Budapesti Street, Szeged, 6728, Hungary
Krisztián Szigeti
Department of Biophysics and Radiation Biology, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary; Hungarian Centre of Excellence for Molecular Medicine, 9 Budapesti Street, Szeged, 6728, Hungary
Péter Nagy
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, 7-9 Rath Gyorgy Street, Budapest, 1122, Hungary; Chemistry Institute, University of Debrecen, 1 Egyetem Square, Debrecen, 4032, Hungary; Department of Anatomy and Histology, HUN-REN–UVMB Laboratory of Redox Biology Research Group, University of Veterinary Medicine, 2 Istvan Street, Budapest, 1078, Hungary
Ildikó Szatmári
Pediatric Centre, MTA Centre of Excellence, Semmelweis University, 53-54 Bokay Janos Street, Budapest, 1083, Hungary
Csaba Fekete
Laboratory for Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, 43 Szigony Street, Budapest, 1083, Hungary
Tamás Arányi
Department of Molecular Biology, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary; HUN-REN Research Centre for Natural Sciences, Institute of Molecular Life Sciences, 2 Magyar Tudosok Boulevard, Budapest, 1117, Hungary
Zoltán V. Varga
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; Center for Pharmacology, Drug Research and Development, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary
Péter Ferdinandy
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; Center for Pharmacology, Drug Research and Development, Semmelweis University, 4 Nagyvarad Square, Budapest, 1089, Hungary; Pharmahungary Group, 6 Hajnoczy Street, Szeged, 6722, Hungary
Zsolt Radák
Research Center for Molecular Exercise Science, Hungarian University of Sport Sciences, 44-48 Alkotas Street, Budapest, 1123, Hungary
Andrey V. Kozlov
Ludwig Boltzmann Institute, 13 Donaueschingenstrasse, Vienna, 1200, Austria
László Tretter
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
Tímea Komlódi
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary; Corresponding author.
Attila Ambrus
Department of Biochemistry, Semmelweis University, 37-47 Tuzolto Street, Budapest, 1094, Hungary
The alpha-ketoglutarate dehydrogenase complex (KGDHc), also known as the 2-oxoglutarate dehydrogenase complex, plays a crucial role in oxidative metabolism. It catalyzes a key step in the tricarboxylic acid (TCA) cycle, producing NADH (primarily for oxidative phosphorylation) and succinyl-CoA (for substrate-level phosphorylation, among others). Additionally, KGDHc is also capable of generating reactive oxygen species, which contribute to mitochondrial oxidative stress. Hence, the KGDHc and its dysfunction are implicated in various pathological conditions, including selected neurodegenerative diseases. The pathological roles of KGDHc in these diseases are generally still obscure.The aim of this study was to assess whether the mitochondrial malfunctions observed in the dihydrolipoamide succinyltransferase (DLST) and dihydrolipoamide dehydrogenase (DLD) double-heterozygous knockout (DLST+/−DLD+/−, DKO) mice are associated with neuronal and/or metabolic abnormalities.In the DKO animals, the mitochondrial O2 consumption and ATP production rates both decreased in a substrate-specific manner. Reduced H2O2 production was also observed, either due to Complex I inhibition with α-ketoglutarate or reverse electron transfer with succinate, which is significant in ischaemia-reperfusion injury. Middle-aged DKO mice exhibited minor cognitive decline, associated with microgliosis in the cerebral cortex and neuronal death in the Cornu Ammonis subfield 1 (CA1) of the hippocampus, indicating neuroinflammation. This was supported by increased levels of dynamin-related protein 1 (Drp1) and reduced levels of mitofusin 2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in DKO mice. Observations on activity, food and oxygen consumption, and blood amino acid and acylcarnitine profiles revealed no significant differences. However, middle-aged DKO animals showed decreased performance in the treadmill fatigue-endurance test as compared to wild-type animals, accompanied by subtle resting cardiac impairment, but not skeletal muscle fibrosis.In conclusion, DKO animals compensate well the double-heterozygous knockout condition at the whole-body level with no major phenotypic changes under resting physiological conditions. However, under high energy demand, middle-aged DKO mice exhibited reduced performance, suggesting a decline in metabolic compensation. Additionally, microgliosis, neuronal death, decreased mitochondrial biogenesis, and altered mitochondrial dynamics were observed in DKO animals, resulting in minor cognitive decline. This is the first study to highlight the in vivo changes of this combined genetic modification. It demonstrates that unlike single knockout rodents, double knockout mice exhibit phenotypical alterations that worsen under stress situations.
