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Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD

Escudero, Silvia, Zaganjor, Elma, Lee, Susan, Mill, Christopher P., Morgan, Ann M., Crawford, Emily B., Chen, Jiahao, Wales, Thomas E., Mourtada, Rida, Luccarelli, James, Bird, Gregory H., Steidl, Ulrich, Engen, John R., Haigis, Marcia C., Opferman, Joseph T., Walensky, Loren D.
Molecular cell 2018 v.69 no.5 pp. 729-743.e7
Food and Agriculture Organization, acyl-CoA dehydrogenase, beta oxidation, blood serum, enzyme activity, gain-of-function mutation, homeostasis, humans, mitochondria, neoplasms, palmitic acid, proteomics, titration
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.