Role of mitochondrial acyl-CoA dehydrogenases in the metabolism of dicarboxylic fatty acids.

Sivakama S Bharathi, Yuxun Zhang, Zhenwei Gong, Radhika Muzumdar, Eric S Goetzman

Biochemical and biophysical research communications 2020 Jun 18

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Dicarboxylic fatty acids, taken as a nutritional supplement or produced endogenously via omega oxidation of monocarboxylic fatty acids, may have therapeutic potential for rare inborn errors of metabolism as well as common metabolic diseases such as type 2 diabetes. Breakdown of dicarboxylic acids yields acetyl-CoA and succinyl-CoA as products, the latter of which is anaplerotic for the TCA cycle. However, little is known about the metabolic pathways responsible for degradation of dicarboxylic acids. Here, we demonstrated with whole-cell fatty acid oxidation assays that both mitochondria and peroxisomes contribute to dicarboxylic acid degradation. Several mitochondrial acyl-CoA dehydrogenases were tested for activity against dicarboxylyl-CoAs. Medium-chain acyl-CoA dehydrogenase (MCAD) exhibited activity with both six and 12 carbon dicarboxylyl-CoAs, and the capacity for dehydrogenation of these substrates was significantly reduced in MCAD knockout mouse liver. However, when dicarboxylic acids were fed to normal mice, the expression of MCAD did not change, while expression of peroxisomal fatty acid oxidation enzymes was greatly upregulated. In conclusion, mitochondrial fatty acid oxidation, and in particular MCAD, contributes to dicarboxylic acid degradation, but feeding dicarboxylic acids induces only the peroxisomal pathway. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Sivakama S Bharathi, Yuxun Zhang, Zhenwei Gong, Radhika Muzumdar, Eric S Goetzman. Role of mitochondrial acyl-CoA dehydrogenases in the metabolism of dicarboxylic fatty acids. Biochemical and biophysical research communications. 2020 Jun 18;527(1):162-166