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Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis

ABSTRACT: Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. Recently a patient with MTO1 gene mutation presented with severe anemia was reported, which led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis, which induced an unfolded protein response via the IRE1-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This novel non-energy-related mitochondrial iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in hematopoiesis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Michal Levin

LAB HEAD: Falk Butter

PROVIDER: PXD054386 | Pride | 2025-01-20

REPOSITORIES: pride

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			Action	DRS
	20200108_SFB1_FBU_VS_BM_ProE_1.raw	Raw
	20200108_SFB1_FBU_VS_BM_ProE_2.raw	Raw
	20200108_SFB1_FBU_VS_BM_ProE_3.raw	Raw
	20200108_SFB1_FBU_VS_BM_baso_1.raw	Raw
	20200108_SFB1_FBU_VS_BM_baso_2.raw	Raw

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