Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.

Oxaloacetate (OAA) is converted to aspartate by mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) along with the conversion of glutamate to alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. In past work, we found that in skeletal muscle mitochondria energized by succinate alone, oxaloacetate accumulates and inhibits succinate dehydrogenase (complex II) in a manner dependent on inner membrane potential (ΔΨ). Here, we tested the hypothesis that deleting GOT2 would increase OAA concentrations, decrease complex II-energized respiration, and alter the selectivity of succinate versus glutamate for energy. Incubating wild-type mitochondria with succinate and glutamate revealed that increments in ADP increased OAA and caused a preferential use of glutamate for energy. Deletion of GOT2 compared to wild-type decreased complex II energized respiration, increased OAA, and decreased consumption of glutamate relative to succinate. OAA accumulation was also associated with decreased conversion of succinate to fumarate and malate. These findings are consistent with GOT2 control of metabolite flow through succinate dehydrogenase via regulation of OAA and consequent inhibition of succinate dehydrogenase. In contrast to respiration energized at complex II, when mitochondria were energized at complex I by pyruvate + malate, respiration did not differ between GOT2KO and WT mitochondria, and oxaloacetate was not detectable. In summary, GOT2 and OAA mediate complex II respiration and mitochondrial energy substrate selectivity.