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Published on: March 15, 2024
Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2
Yanhong Zhang1, Yingjuan Qian1,2, Jin Zhang1
1Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California 95616, USA.
Abstract:
Ferredoxin reductase (FDXR), a target of p53, modulates p53-dependent apoptosis and is necessary for steroidogenesis and biogenesis of iron-sulfur clusters. To determine the biological function of FDXR, we generated a Fdxr-deficient mouse model and found that loss of Fdxr led to embryonic lethality potentially due to iron overload in developing embryos. Interestingly, mice heterozygous in Fdxr had a short life span and were prone to spontaneous tumors and liver abnormalities, including steatosis, hepatitis, and hepatocellular carcinoma. We also found that FDXR was necessary for mitochondrial iron homeostasis and proper expression of several master regulators of iron metabolism, including iron regulatory protein 2 (IRP2). Surprisingly, we found that p53 mRNA translation was suppressed by FDXR deficiency via IRP2. Moreover, we found that the signal from FDXR to iron homeostasis and the p53 pathway was transduced by ferredoxin 2, a substrate of FDXR. Finally, we found that p53 played a role in iron homeostasis and was required for FDXR-mediated iron metabolism. Together, we conclude that FDXR and p53 are mutually regulated and that the FDXR-p53 loop is critical for tumor suppression via iron homeostasis.
Insights
Ferredoxin reductase (FDXR) deficiency causes embryonic lethality and liver tumors in mice by disrupting iron homeostasis and the p53 pathway. This study reveals a critical FDXR-p53 loop essential for tumor suppression.
Area of Science:
- Molecular Biology
- Iron Metabolism
- Cancer Biology
Background:
- Ferredoxin reductase (FDXR) is a p53 target involved in apoptosis, steroidogenesis, and iron-sulfur cluster biogenesis.
- The precise biological role of FDXR, particularly its connection to p53 and iron metabolism, remains incompletely understood.
Purpose of the Study:
- To elucidate the biological functions of FDXR and its role in regulating p53 and iron homeostasis.
- To investigate the consequences of FDXR deficiency in a mammalian model.
Main Methods:
- Generation and analysis of a Fdxr-deficient mouse model.
- Assessment of embryonic lethality, lifespan, tumor development, and liver abnormalities.
- Investigation of mitochondrial iron homeostasis, p53 mRNA translation, and iron regulatory protein 2 (IRP2) expression.
Main Results:
- Fdxr deficiency resulted in embryonic lethality, likely due to iron overload.
- Heterozygous Fdxr mice exhibited shortened lifespans, spontaneous tumors, and liver pathologies (steatosis, hepatitis, hepatocellular carcinoma).
- FDXR is crucial for mitochondrial iron homeostasis, IRP2 expression, and p53 mRNA translation, with ferredoxin 2 acting as a key mediator.
Conclusions:
- FDXR and p53 are mutually regulated, forming a critical loop for tumor suppression via iron homeostasis.
- The FDXR-p53-iron homeostasis axis represents a novel pathway in cancer biology.
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