Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells

The role of mitochondria in the fate determination of hematopoietic stem and progenitor cells (HSPCs) is not solely limited to the switch from glycolysis to oxidative phosphorylation, but also involves alterations in mitochondrial features and properties, including mitochondrial membrane potential (ΔΨ_mt). HSPCs have a high ΔΨ_mt even when the rates of respiration and phosphorylation are low, and we have previously shown that the minimum proton flow through ATP synthesis (or complex V) enables high ΔΨ_mt in HSPCs. Here we show that HSPCs sustain a unique equilibrium between electron transport chain (ETC) complexes and ATP production. HSPCs exhibit high expression of ETC complex II, which sustains complex III in proton pumping, although the expression levels of complex I or V are relatively low. Complex II inhibition by TTFA caused a substantial decrease of ΔΨ_mt, particularly in HSPCs, while the inhibition of complex I by Rotenone mainly affected mature populations. Functionally, pharmacological inhibition of complex II reduced in vitro colony-replating capacity but this was not observed when complex I was inhibited, which supports the distinct roles of complex I and II in HSPCs. Taken together, these data highlight complex II as a key regulator of ΔΨ_mt in HSPCs and open new and interesting questions regarding the precise mechanisms that regulate mitochondrial control to maintain hematopoietic stem cell self-renewal.