| First Author | Wright T | Year | 2024 |
| Journal | Mol Cell | Volume | 84 |
| Issue | 7 | Pages | 1338-1353.e8 |
| PubMed ID | 38503284 | Mgi Jnum | J:347662 |
| Mgi Id | MGI:7621085 | Doi | 10.1016/j.molcel.2024.02.035 |
| Citation | Wright T, et al. (2024) Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1. Mol Cell 84(7):1338-1353.e8 |
| abstractText | 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 beta-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. |
