Hepatic glutamic-oxaloacetic transaminase promotes mitochondrial respiration energized at complex II and alters whole body metabolism.

The mitochondrial enzyme, glutamic-oxaloacetic transaminase (GOT2), catalyzes the reaction between oxaloacetate and glutamate generating aspartate and alpha-ketoglutarate. Glutamate can also be directly converted to alpha-ketoglutarate by glutamate dehydrogenase. We investigated mitochondrial and systemic effects of an inducible liver-specific mouse GOT2 knockout (KO). We observed no differences in body mass or percent fat mass in KO mice; however, KO mice had lower fasting glucose and liver tissue contained more fat. Respiration by liver mitochondria energized at complex II by succinate + glutamate was decreased in KO compared to WT mice at low inner membrane potential (ΔΨ) as induced by titration with ADP. Metabolite studies by NMR showed that at low versus high ΔΨ, GOT2KO mitochondria energized by succinate + glutamate generated more oxaloacetate (a potent inhibitor of succinate dehydrogenase) and less aspartate. Respiration and mitochondrial metabolites energized by pyruvate + malate or palmitoyl-carnitine + malate did not differ between KO and WT mice. Respiration by GOT2KO mitochondria energized by glutamate + malate was decreased at all levels of ΔΨ. Pathway analysis of LC-MS profile data in the liver tissue of KO versus WT mice revealed differential enrichment of the malate aspartate shuttle, TCA cycle, aspartate metabolism, glutamate metabolism, and gluconeogenesis. In summary, GOT2KO impaired potential-dependent complex II energized O flux likely due at least in part to oxaloacetate inhibition of succinate dehydrogenase.