Glutamate dehydrogenase is essential to sustain neuronal oxidative energy metabolism during stimulation

TLDR

Glutamate dehydrogenase (GDH) catalyzes the reversible oxidative deamination of glutamate to α‑ketoglutarate, linking amino‑acid, carbohydrate, neurotransmitter, and oxidative energy metabolism, and neurons use glutamine both as a neurotransmitter precursor and a source of oxidative energy. This study investigates the role of GDH in neuronal metabolism using a brain‑specific GDH knockout mouse and 13C‑labelled metabolic mapping. The authors employed Cns‑Glud1‑/‑ mice lacking GDH in the brain and performed metabolic mapping with 13C‑labelled glutamine and glucose in synaptosomes and cultured neurons. GDH deficiency severely impairs oxidative glutamine metabolism during glucose deprivation, reduces glutamate‑driven respiration, and prevents synaptosomes from increasing respiration under elevated energy demand, highlighting GDH’s essential role during high energy demand.

Abstract

The enzyme glutamate dehydrogenase (GDH; Glud1) catalyzes the (reversible) oxidative deamination of glutamate to α-ketoglutarate accompanied by a reduction of NAD+ to NADH. GDH connects amino acid, carbohydrate, neurotransmitter and oxidative energy metabolism. Glutamine is a neurotransmitter precursor used by neurons to sustain the pool of glutamate, but glutamine is also vividly oxidized for support of energy metabolism. This study investigates the role of GDH in neuronal metabolism by employing the Cns- Glud1-/- mouse, lacking GDH in the brain (GDH KO) and metabolic mapping using 13C-labelled glutamine and glucose. We observed a severely reduced oxidative glutamine metabolism during glucose deprivation in synaptosomes and cultured neurons not expressing GDH. In contrast, in the presence of glucose, glutamine metabolism was not affected by the lack of GDH expression. Respiration fuelled by glutamate was significantly lower in brain mitochondria from GDH KO mice and synaptosomes were not able to increase their respiration upon an elevated energy demand. The role of GDH for metabolism of glutamine and the respiratory capacity underscore the importance of GDH for neurons particularly during an elevated energy demand, and it may reflect the large allosteric activation of GDH by ADP.