2. Academic Validation
  3. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1

Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1

  • Mol Cell. 2024 Mar 11:S1097-2765(24)00176-X. doi: 10.1016/j.molcel.2024.02.035.
Tristen Wright 1,  Meghan E Turnis 2,  Christy R Grace 3,  Xiao Li 2,  Lauren A Brakefield 4,  Yong-Dong Wang 2,  Haiyan Xu 2,  Ewa Kaminska 2,  Leslie K Climer 2,  Tresor O Mukiza 2,  Chi-Lun Chang 2,  Tudor Moldoveanu 3,  Joseph T Opferman 5
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • 5 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: joseph.opferman@stjude.org.
PMID: 38503284 DOI: 10.1016/j.molcel.2024.02.035
Abstract

Mcl-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in Cancer. Beyond Apoptosis regulation, Mcl-1 has been linked to modulating Mitochondrial Metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that Mcl-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of Mcl-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic Mcl-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic Mcl-1 facilitates Mitochondrial Metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of Mcl-1 inhibitors in clinical trials.

Keywords

MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation.

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