Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.

Abstract

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.