Research ReportExperimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload

•Brain bioenergetics and histopathology were evaluated in brain of Gcdh−/− mice.•Mild alterations of energy homeostasis were observed in the striatum of 30-day-old Gcdh−/− mice.•Cerebral cortex and striatum of adult Gcdh−/− mice showed intense vacuolation.•Brain injury cannot be solely attributed to bioenergetics impairment in Gcdh−/− mice.

Bioenergetics dysfunction has been postulated as an important pathomechanism of brain damage in glutaric aciduria type I, but this is still under debate. We investigated activities of citric acid cycle (CAC) enzymes, lactate release, respiration and membrane potential (ΔΨm) in mitochondrial preparations from cerebral cortex and striatum of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh−/−) and wild type mice fed a baseline or a high lysine (Lys, 4.7%) chow for 60 or 96 h. Brain histological analyses were performed in these animals, as well as in 90-day-old animals fed a baseline or a high Lys chow during 30 days starting at 60-day-old. A moderate reduction of citrate synthase and isocitrate dehydrogenase activities was observed only in the striatum from 30-day-old Gcdh−/− animals submitted to a high Lys chow. In contrast, the other CAC enzyme activities, lactate release, the respiratory parameters state 3, state 4, the respiratory control ratio and CCCP-stimulated (uncoupled) state, as well as ΔΨm were not altered in the striatum. Similarly, none of the evaluated parameters were changed in the cerebral cortex from these animals under baseline or Lys overload. On the other hand, histological analyses revealed the presence of intense vacuolation in the cerebral cortex of 60 and 90-day-old Gcdh−/− mice fed a baseline chow and in the striatum of 90-day-old Gcdh−/− mice submitted to Lys overload for 30 days. Taken together, the present data demonstrate mild impairment of bioenergetics homeostasis and marked histological alterations in striatum from Gcdh−/− mice under a high Lys chow, suggesting that disruption of energy metabolism is not mainly involved in the brain injury of these animals.