Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1

作者：Leisi Zhang, Honghai Zhang, Ting‐Yu Wang, Mingli Li, Anthony Chan, HyunJun Kang, Lai C. Foong, Qiao Liu, Sheela Pangeni Pokharel, Nicole M. Mattson, Priyanka Singh, Zeinab Elsayed, Benjamin Kuang, Xueer Wang, Steven T. Rosen, Jianjun Chen, Lu Yang, Tsui‐Fen Chou, Rui Su, Chun‐Wei Chen · 发表于：Advanced Science · 年份：2024 · DOI：10.1002/advs.202404620 · 被引用次数：8 · 研究领域：Advanced biosensing and bioanalysis techniques、Acute Myeloid Leukemia Research、Protein Degradation and Inhibitors

Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. This study highlights COX4I1, a nuclear encoded mitochondrial protein, as a critical mitochondrial checkpoint, offering insights into its functional significance and potential clinical implications in AML.