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Mol Cell. 2018 Mar 1;69(5):729-743.e7. doi: 10.1016/j.molcel.2018.02.005.

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

Author information

1
Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
5
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
6
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: joseph.opferman@stjude.org.
7
Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: loren_walensky@dfci.harvard.edu.

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.

KEYWORDS:

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

PMID:
29499131
PMCID:
PMC5916823
DOI:
10.1016/j.molcel.2018.02.005
[Indexed for MEDLINE]
Free PMC Article

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