Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis
Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (<i>Mto1</i>) is essential for the mitochondrial protein translation. <i>Mto1</i> deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with <i>MTO1</i> gene mutation showed severe anemia led us to hypothesize that <i>Mto1</i> dysfunctions may result in defective erythropoiesis. Hematopoietic-specific <i>Mto1</i> conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the <i>Mto1</i> cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in <i>Mto1</i> cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the <i>Mto1</i> cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
Authors
- Vivien A. C. Schoonenberg (ORCID: https://orcid.org/0000-0002-7865-7120)
- Yuichiro Arima (ORCID: https://orcid.org/0000-0002-9840-3347)
- Fan‐Yan Wei (ORCID: https://orcid.org/0000-0002-4843-724X)
- Falk Butter (ORCID: https://orcid.org/0000-0002-7197-7279)
- Takeshi Masuda (ORCID: https://orcid.org/0000-0003-0121-4783)
- Kazuhito Tomizawa (ORCID: https://orcid.org/0000-0002-5663-2627)
- Toshio Suda (ORCID: https://orcid.org/0000-0001-7540-1771)
- Hitoshi Takizawa (ORCID: https://orcid.org/0000-0002-5276-5430)
- Akiko Ogawa (ORCID: https://orcid.org/0009-0000-9837-2010)
- Toshiro Moroishi (ORCID: https://orcid.org/0000-0001-6419-3882)
- Takaaki Akaike (ORCID: https://orcid.org/0000-0002-0623-1710)
- Md. Fakruddin (ORCID: https://orcid.org/0000-0003-2720-9173)
- Yohei Kanamori (ORCID: https://orcid.org/0009-0003-4062-5910)
- Yuxin Wang (ORCID: https://orcid.org/0000-0002-1629-4176)
- Tatsuya Morishima (ORCID: https://orcid.org/0000-0003-3876-3217)
Institutions
- Kumamoto Health Science University (JP)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Tohoku University (JP)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Institute of Molecular Biology (DE)
- Kumamoto University (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1126/sciadv.adu3011
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61