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

Molecular cell 2024 Apr 04

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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. Copyright © 2024 Elsevier Inc. All rights reserved.

Citation

Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1. Molecular cell. 2024 Apr 04;84(7):1338-1353.e8