Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis

Abstract

AbstractA lack of the mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) was recently shown to induce proteostress in embryonic stem cells. Since erythroid precursors actively synthesize the hemoglobin protein, we hypothesized thatMto1dysfunctions may result in defective erythropoiesis. Hematopoietic-specificMto1conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complex-I was severely defective in theMto1cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis and enhanced the expression of embryonic hemoglobin proteins, which induced an unfolded protein response via the IRE1α-Xbp1 signaling pathway inMto1cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in theMto1cKO fetal liverin vitro. The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research.