Compartmentation of Metabolism of the C12-, C9-, and C5-n-dicarboxylates in Rat Liver, Investigated by Mass Isotopomer Analysis: ANAPLEROSIS FROM DODECANEDIOATE.

Abstract

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 (13)C-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.

• Authors: Zhicheng Jin, Fang Bian, Kristyen Tomcik, Joanne K Kelleher, Guo-Fang Zhang, Henri Brunengraber
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 30 Pg. 18671-7 (Jul 24 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26070565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Dicarboxylic Acids
• Fatty Acids
• Glutarates
• Malonyl Coenzyme A
• dodecanedioic acid
• Coenzyme A

Topics

• Amino Acid Metabolism, Inborn Errors (diet therapy, drug therapy, genetics, metabolism)
• Animals
• Citric Acid Cycle (genetics)
• Coenzyme A (metabolism)
• Dicarboxylic Acids (metabolism)
• Fatty Acids (genetics, metabolism)
• Glutarates (metabolism)
• Humans
• Liver (metabolism, pathology)
• Malonyl Coenzyme A (metabolism)
• Metabolism, Inborn Errors (drug therapy, genetics, metabolism)
• Mitochondria (metabolism)
• Myocardium (metabolism, pathology)
• Oxidation-Reduction
• Peroxisomes (metabolism)
• Propionic Acidemia (diet therapy, drug therapy, genetics, metabolism)
• Rats