Li H, Hurlburt AJ, Tennessen JM. A Drosophila model of combined D-2- and L-2-hydroxyglutaric aciduria reveals a mechanism linking mitochondrial citrate export with oncometabolite accumulation. Dis Model Mech. 2018 Sep 21;11(9). PMID: 30108060; PMCID: PMC6177012.
From the abstract: "The enantiomers of 2-hydroxyglutarate (2HG) are potent regulators of metabolism, chromatin modifications and cell fate decisions. ... The metabolic mechanisms that control 2HG metabolism in vivo are poorly understood. One clue towards how cells regulate 2HG levels has emerged from an inborn error of metabolism known as combined D- and L-2HG aciduria (D-/L-2HGA), which results in elevated D- and L-2HG accumulation. Because this disorder is caused by mutations in the mitochondrial citrate transporter (CIC), citrate must somehow govern 2HG metabolism in healthy cells. ... Here, we use the fruit fly Drosophila melanogaster to elucidate a metabolic link between citrate transport and L-2HG accumulation. Our study reveals that the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, dampens glycolytic flux and restricts L-2HG accumulation. Moreover, we find that sea mutants accumulate excess L-2HG ... which inhibits L-2HG degradation by interfering with L-2HG dehydrogenase activity. This unexpected result demonstrates that citrate indirectly regulates L-2HG stability and reveals a feedback mechanism that coordinates L-2HG metabolism with glycolysis and the tricarboxylic acid cycle. Finally, our study also suggests a potential strategy for preventing L-2HG accumulation in human patients with CIC deficiency."
No comments:
Post a Comment