Fakruddin, M. | bioRxiv Science

bioRxiv2023

Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis

A 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 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 complex-I was severely defective in the Mto1 cKO 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 IRE1-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research.

cell biology↗

bioRxiv2021

Hematopoietic stem and progenitor cells integrate Bacteroides-derived innate immune signals to promote gut tissue repair

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated by bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we showed that acute gut inflammation expands HSPCs in the BM through GM-CSFR activation, and directs them to inflamed mesenteric lymph nodes for further differentiation into myeloid cells specialized in gut tissue repair. We also identified that this process is exclusively mediated by Bacteroides, a commensal gram-negative bacteria, that activates innate immune signaling. In contrast, chronic gut inflammation reduces HSC potential for hematopoietic reconstitution and immune response against infection. Similarly, microbial signals contribute to aging-associated HSPC expansion. These findings establish a cross-organ communication that promotes tissue regeneration, but if sustained, impairs tissue homeostasis that may be relevant to aging and chronic disorders. SummaryThe infiltrating microbiota Bacteroides upon acute colitis directed MPP migration from the BM to the MLN for their subsequent expansion and differentiation into tissue-repairing Ly6C+/G+ cells, whereas chronic colitis impairs HSC functionality similarly as aging.

pathology↗