Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1
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.
Authors
- Anthony Chan (ORCID: https://orcid.org/0000-0002-7091-1294)
- Ting‐Yu Wang (ORCID: https://orcid.org/0000-0002-9014-6825)
- Steven T. Rosen (ORCID: https://orcid.org/0000-0002-8818-7724)
- Tsui‐Fen Chou (ORCID: https://orcid.org/0000-0003-2410-2186)
- Nicole M. Mattson (ORCID: https://orcid.org/0000-0001-5881-3387)
- Priyanka Singh (ORCID: https://orcid.org/0000-0002-5288-2290)
- Leisi Zhang
- Chun‐Wei Chen (ORCID: https://orcid.org/0000-0002-8737-6830)
- Sheela Pangeni Pokharel (ORCID: https://orcid.org/0000-0003-2822-8659)
- Lu Yang (ORCID: https://orcid.org/0000-0001-6223-8995)
- Xueer Wang
- Benjamin Kuang (ORCID: https://orcid.org/0000-0002-0944-0753)
- Qiao Liu (ORCID: https://orcid.org/0000-0002-6620-1994)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- Rui Su (ORCID: https://orcid.org/0000-0002-4807-6229)
- Honghai Zhang (ORCID: https://orcid.org/0000-0002-5010-2502)
- HyunJun Kang
- Mingli Li (ORCID: https://orcid.org/0000-0001-6921-3651)
- Zeinab Elsayed (ORCID: https://orcid.org/0009-0009-3202-5601)
- Lai C. Foong
Institutions
- California Institute of Technology (US)
- Soochow University (CN)
- City of Hope (US)
- First Affiliated Hospital of Soochow University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1002/advs.202404620
- Citations
- 5
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- American Society of Hematology
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Leukemia Research Foundation
- Stand Up To Cancer