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

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.