TY - JOUR
T1 - Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells
AU - Morganti, Claudia
AU - Bonora, Massimo
AU - Ito, Kyoko
AU - Ito, Keisuke
N1 - Funding Information:
The authors thank all members of the Ito laboratory, especially H Sato, and the Einstein Stem Cell Institute for comments and the Einstein Flow Cytometry and Analytical Imaging core facilities (funded by National Cancer Institute grant P30 CA013330) for help carrying out the experiments. Ke.I. is supported by grants from the National Institutes of Health (R01DK98263, R01DK115577, and R01HL148852) and the New York State Department of Health as Core Director of Einstein Single-Cell Genomics/Epigenomics (C029154). Ke. I. is a Research Scholar of the Leukemia and Lymphoma Society (1360-19). C.M. is supported by NYSTEM Einstein Training Program in Stem Cell Research. Support for The Einstein Training Program in Stem Cell Research of Albert Einstein College of Medicine, Inc. is acknowledged from the Empire State Stem Cell Fund through New York State Department of Health Contract C30292GG. Opinions expressed here are solely those of the author and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York.
Funding Information:
The authors thank all members of the Ito laboratory, especially H Sato, and the Einstein Stem Cell Institute for comments and the Einstein Flow Cytometry and Analytical Imaging core facilities (funded by National Cancer Institute grant P30 CA013330 ) for help carrying out the experiments. Ke.I. is supported by grants from the National Institutes of Health ( R01DK98263 , R01DK115577 , and R01HL148852 ) and the New York State Department of Health as Core Director of Einstein Single-Cell Genomics/Epigenomics ( C029154 ). Ke. I. is a Research Scholar of the Leukemia and Lymphoma Society ( 1360-19 ). C.M. is supported by NYSTEM Einstein Training Program in Stem Cell Research. Support for The Einstein Training Program in Stem Cell Research of Albert Einstein College of Medicine, Inc. is acknowledged from the Empire State Stem Cell Fund through New York State Department of Health Contract C30292GG. Opinions expressed here are solely those of the author and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York.
Publisher Copyright:
© 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - 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 (ΔΨmt). HSPCs have a high ΔΨmt 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 ΔΨmt 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 ΔΨmt, 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 ΔΨmt in HSPCs and open new and interesting questions regarding the precise mechanisms that regulate mitochondrial control to maintain hematopoietic stem cell self-renewal.
AB - 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 (ΔΨmt). HSPCs have a high ΔΨmt 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 ΔΨmt 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 ΔΨmt, 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 ΔΨmt in HSPCs and open new and interesting questions regarding the precise mechanisms that regulate mitochondrial control to maintain hematopoietic stem cell self-renewal.
KW - ATP synthase
KW - Electron transport chain
KW - HSC
KW - Mitochondrial membrane potential
KW - SDHA
KW - TMRM
UR - http://www.scopus.com/inward/record.url?scp=85072204547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072204547&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2019.101573
DO - 10.1016/j.scr.2019.101573
M3 - Article
C2 - 31539857
AN - SCOPUS:85072204547
SN - 1873-5061
VL - 40
JO - Stem Cell Research
JF - Stem Cell Research
M1 - 101573
ER -