Zhicheng Jin, F. Bian, Kristyen A. Tomcik
Jun 12, 2015
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Influential Citations
17
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Journal
The Journal of Biological Chemistry
Abstract
Background: We explored the compartmentation of n-dicarboxylate liver catabolism. Results: Dodecanedioate and azelate oxidation span peroxisomes and mitochondria; glutarate oxidation is mitochondrial; dodecanedioate is anaplerotic. Conclusion: Dodecanedioate is a potential substrate for anaplerotic therapy of reperfusion injury and some inborn disorders of metabolism. Significance: This metabolomic + mass isotopomer strategy can be used to better characterize substrate catabolism in disease models. We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate, and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully 13C-labeled dicarboxylate. Information on the peroxisomal versus mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e. total acetyl-CoA, the acetyl moiety of citrate, C-1 + 2 of β-hydroxybutyrate, malonyl-CoA, and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g. in propionic acidemia and methylmalonic acidemia.