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

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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.

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Acknowledgments

This work was supported by funding from the Russian Foundation of Basic Research (grants 10-04-90007, 11-04-91154 and 12-04-01541 to V.B.) and the Max Planck Society (WLA and ARF).

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Authors and Affiliations

  1. Max-Planck-Institut für Molekulare Pflanzenphysiologie, 14476, Potsdam-Golm, Germany

    Wagner L. Araújo, Dirk Steinhauser, Leonard Krall & Alisdair R. Fernie

  2. Departamento de Biologia Vegetal, Universidade Federal de Viçosa, Viçosa, MG, 36570-000, Brazil

    Wagner L. Araújo

  3. Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    Lidia Trofimova & Anastasia Graf

  4. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia

    Garik Mkrtchyan & Victoria I. Bunik

  5. A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    Victoria I. Bunik

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  1. Wagner L. Araújo
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  2. Lidia Trofimova
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Araújo, W.L., Trofimova, L., Mkrtchyan, G. et al. On the role of the mitochondrial 2-oxoglutarate dehydrogenase complex in amino acid metabolism. Amino Acids 44, 683–700 (2013). https://doi.org/10.1007/s00726-012-1392-x

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