Adv Sci (Weinh). 2024 Dec 23. e2404620
Leisi Zhang,
Honghai Zhang,
Ting-Yu Wang,
Mingli Li,
Anthony K N 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 David Chen.
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.
Keywords: COX4I1; chlorpromazine; leukemia; mitochondria; venetoclax