On the role of the mitochondrial 2-oxoglutarate dehydrogenase complex in amino acid metabolism

Abstract

Mitochondria are tightly linked to cellular nutrient sensing, and provide not only energy, but also intermediates for the de novo synthesis of cellular compounds including amino acids. Mitochondrial metabolic enzymes as generators and/or targets of signals are therefore important players in the distribution of intermediates between catabolic and anabolic pathways. The highly regulated 2-oxoglutarate dehydrogenase complex (OGDHC) participates in glucose oxidation via the tricarboxylic acid cycle. It occupies an amphibolic branch point in the cycle, where the energy-producing reaction of the 2-oxoglutarate degradation competes with glutamate (Glu) synthesis via nitrogen incorporation into 2-oxoglutarate. To characterize the specific impact of the OGDHC inhibition on amino acid metabolism in both plant and animal mitochondria, a synthetic analog of 2-oxoglutarate, namely succinyl phosphonate (SP), was applied to living systems from different kingdoms, both in situ and in vivo. Using a high-throughput mass spectrometry-based approach, we showed that organisms possessing OGDHC respond to SP by significantly changing their amino acid pools. By contrast, cyanobacteria which lack OGDHC do not show perturbations in amino acids following SP treatment. Increases in Glu, 4-aminobutyrate and alanine represent the most universal change accompanying the 2-oxoglutarate accumulation upon OGDHC inhibition. Other amino acids were affected in a species-specific manner, suggesting specific metabolic rearrangements and substrate availability mediating secondary changes. Strong perturbation in the relative abundance of amino acids due to the OGDHC inhibition was accompanied by decreased protein content. Our results provide specific evidence of a considerable role of OGDHC in amino acid metabolism.

Genome-wide identification of genes probably relevant to the adaptation of schizothoracins (Teleostei: Cypriniformes) to the uplift of the Qinghai-Tibet Plateau

“…Thus, the “dab2 interacting protein” ( dab2ip ) gene, which suppresses the development of many cancer types [43], likely appeared among the SH genes for this reason. Meanwhile, some genes relevant to energy metabolism, for example, the “2-oxoglutarate dehydrogenase” ( ogdh ) [44] and atp6v0a1 genes, participate in the “oxidative phosphorylation” pathway and probably contributed to adaptation to the reduced water temperature.…”

The non-metabolizable glucose analog D-glucal inhibits aflatoxin biosynthesis and promotes kojic acid production in Aspergillus flavus

“…We thus speculate that sugar analogs that are unable to be utilized by A. flavus are candidate inhibitors for AF biosynthesis. Chemical analogs are often used to inhibit metabolism, as they may bind competitively to the active or allosteric sites of enzymes and hamper their activities [10,11]. Three glucose analogs, 2-deoxyglucose, α-methyglucoside and glucosamine, have been tested in A. parasiticus previously, but none of them inhibited AF production when applied to a glucose-containing medium [12].…”

Amplification of USP13 drives ovarian cancer metabolism

“…As examples, upregulation of OGDH was identified as a driver for hepatocellular carcinoma29. Recent studies also reported that targeting the α-KGDH complex inhibits amino-acid metabolism and regulates oxidative stress in cancer cells1330. Inhibition of OGDH leads to buildup of lactic acid and suppresses cell growth1531.…”