MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.

MCL-1 是一种抗凋亡 BCL-2 家族蛋白，对于多种细胞类型的存活至关重要，并且是癌症和化学抗性的主要驱动因素。MCL-1 在其抗凋亡同系物中的致癌优势的机制基础尚不清楚，并且暗示 MCL-1 的生理作用超出了凋亡抑制。在这里，我们发现 MCL-1 依赖性血液癌细胞特别依赖脂肪酸氧化 (FAO) 作为燃料来源，因为 MCL-1 本身强制执行代谢连接。基于缺乏完整凋亡途径的 MCL-1 依赖性白血病细胞的代谢组学、蛋白质组学和基因组学分析，我们证明了 MCL-1 对 FAO 的调节与其抗凋亡活性无关。Mcl-1基因缺失导致 FAO 通路蛋白的转录下调，因此尽管细胞凋亡被阻断，但葡萄糖的减少会引发细胞死亡。我们的数据显示 MCL-1 是 FAO 的主要调节因子，使 MCL-1 驱动的癌细胞特别容易受到 FAO 抑制剂治疗的影响。