Abstract
The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.
Highlights
The metabolic state of stem cells is emerging as an important determinant of their fate
More recently we demonstrated that the BH3-interacting domain death agonist (BID) protein acts as a downstream ataxia–telangiectasia mutated (ATM)-effector in this pathway and regulates the quiescence of haematopoietic stem cell (HSC) by balancing reactive oxygen species (ROS) levels produced by mitochondria[14]
Analysing the cell cycle status of MTCH2F/F Vav1-cre þ HSCs and progenitor populations, we observed a reduction in quiescent HSCs (Fig. 1d), which was accompanied by increased proliferation of HSCs, haematopoietic stem and progenitor cells (HSPCs) (Lin À Sca-1 þ c-Kit þ ; LSK) and committed progenitors (Lin À Sca-1 À c-Kit þ ; LK; Fig. 1e)
Summary
The metabolic state of stem cells is emerging as an important determinant of their fate. It is well established that ROS drives HSC entry into cycle, and more recently it has been demonstrated that the transition from stem to progenitor cell corresponds to a metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS)[6,7,8,9,10,11]. The exact mechanism by which BID regulates mitochondrial ROS and its relation to the switch to mitochondrial OXPHOS described in the transition from stem to progenitor cell remained unknown[15] To address this issue, we shifted our focus to mitochondrial carrier homologue 2 (MTCH2), BID’s receptor-like protein in the mitochondria that plays a critical role in Fas-induced liver apoptosis[16]. Similar findings were obtained with our previously described BIDAA mice[14], indicating that MTCH2 is an essential regulator of haematopoietic homeostasis downstream of ATM and BID
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