INTRODUCTION: The brain represents the largest source of energy consumption in our body, most of the energy being primarily utilized at the synapses. Therefore, regulation of metabolite supply and energy metabolism is especially critical to the central nervous system and even subtle changes in energy production may lead to neurological diseases. Indeed, mitochondrial dysfunction was observed in a number of neurodevelopmental disorders. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother.

AIM(S): We generated knock-in Trap1 p.Q641* mice that revealed male-specific social behavior abnormalities accompanied by altered synaptic transmission and dendritic spine morphology. Next, we aimed at investigating mitochondrial metabolism in the synapses of Trap1 mutant mice.

METHOD(S): We performed functional mitochondrial phenotyping using Mitoplates (Biolog). Next, targeted metabolomics was performed to assess levels of amino acids in the brain. Finally, the levels of NAD/NADH were assessed using colorimetric assays.

RESULTS: The functional mitochondrial phenotyping of synaptoneurosomes isolated from mouse brains (cortex and hippocampus) of male and female Trap1 mice revealed differences in the use of the tricarboxylic acid cycle substrates in males but not in females. Morover, our preliminary data suggests that the levels glutamate and GABA are decreased in the hippocampus of male mutant mice, but not in females. Finally, the NAD/NADH ratio was icreased in the hippocampi of Trap1 mutant male, but not female mice.

CONCLUSIONS: Altogether, our results support the previously observed link between dysregulated mitochondrial metabolism and ASD. Moreover, our findings highlight the need for in-depth analysis of both males and females in mouse models of ASD.

FINANCIAL SUPPORT: Supported by the National Science Centre, Poland: OPUS 2023/51/B/NZ4/00856