A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Autor:	Pezacki AT; Department of Chemistry, University of California, Berkeley, CA 94720., Gonciarz RL; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158., Okamura T; Department of Chemistry, University of California, Berkeley, CA 94720., Matier CD; Department of Chemistry, University of California, Berkeley, CA 94720., Torrente L; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612., Cheng K; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158., Miller SG; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239., Ralle M; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239., Ward NP; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612., DeNicola GM; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612., Renslo AR; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158., Chang CJ; Department of Chemistry, University of California, Berkeley, CA 94720.; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 09; Vol. 121 (28), pp. e2401579121. Date of Electronic Publication: 2024 Jul 05.
DOI:	10.1073/pnas.2401579121
Abstrakt:	Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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