Abstract 544: Dissecting the biological functions of various isoforms of ferredoxin reductase for cell survival and DNA damage response.

Abstract The ferredoxin reductase (FDXR) gene is expressed as seven isoforms: 1-6 by alternative splicing and 7 by alternative promoter. FDXR, primarily the reference mitochondrial isoform 1, is required for biosynthesis of sterols, heme and iron-sulfur clusters, but isoforms 2-7 are undefined. Here, we found that isoform 1 is the most abundant one, accounting for ∼70% of total FDXR whereas isoforms 4 and 7 account for ∼10% and ∼7%, respectively. We found that isoforms 1 and 4 are mainly localized in the mitochondria whereas isoform 7, which lacks a mitochondria localization signal, is expressed in the cytosol. We also found that like the promoter for isoforms 1-6, the P2 promoter for isoform 7 can be induced by DNA damage in a p53-dependent manner. To determine isoform-specific activity, we generated multiple MCF7 cell lines in that one or more isoforms are knocked out. While total FDXR-KO MCF7 cells are non-viable, cells deficient in isoforms 1-6, isoforms 4 or 7 remain viable but are weak in cell proliferation, DNA damage response and repair. These data suggest that each FDXR isoform contributes to cell survival and that isoform 7 has an extra-mitochondrial activity sufficient for cell survival. Citation Format: Kenichi Nakajima, Shakur Mohibi, Kyle Kenji Hong, Xinbin Chen, Jin Zhang. Dissecting the biological functions of various isoforms of ferredoxin reductase for cell survival and DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 544.