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

Silvia Escudero, Elma Zaganjor, Susan Lee, Christopher P. Mill, Ann M. Morgan, Emily B. Crawford, Jiahao Chen, Thomas E. Wales, Rida Mourtada, James Luccarelli, Gregory H. Bird, Ulrich Steidl, John R. Engen, Marcia C. Haigis, Joseph T. Opferman, Loren D. Walensky

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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. MCL-1 is a formidable BCL-2 family protein implicated in human cancer and its genetic deletion causes profound physiologic consequences not compensated for by anti-apoptotic homologs. Escudero et al. report that the MCL-1 BH3 α helix directly binds to and modulates VLCAD, revealing a new role for MCL-1 in regulating lipid metabolism.

Original languageEnglish (US)
Pages (from-to)729-743.e7
JournalMolecular Cell
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2018

Keywords

  • BCL-2 family
  • MCL-1
  • VLCAD
  • apoptosis
  • fatty acid metabolism
  • mitochondria
  • mitochondrial matrix
  • stapled peptide
  • α helix
  • β-oxidation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Escudero, S., Zaganjor, E., Lee, S., Mill, C. P., Morgan, A. M., Crawford, E. B., Chen, J., Wales, T. E., Mourtada, R., Luccarelli, J., Bird, G. H., Steidl, U., Engen, J. R., Haigis, M. C., Opferman, J. T., & Walensky, L. D. (2018). Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD. Molecular Cell, 69(5), 729-743.e7. https://doi.org/10.1016/j.molcel.2018.02.005