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

• DOI: 10.1016/j.molcel.2024.02.035
• Publication Date: 2024-03-18T14:28:42Z
• Authors: 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
• Keywords: Fatty Acid Metabolism

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.