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

Claudia Morganti, Massimo Bonora, Kyoko Ito, Keisuke Ito

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number101573
JournalStem Cell Research
Volume40
DOIs
StatePublished - Oct 1 2019

Fingerprint

Electron Transport Complex II
Mitochondrial Membrane Potential
Hematopoietic Stem Cells
Protons
Adenosine Triphosphate

Keywords

  • ATP synthase
  • Electron transport chain
  • HSC
  • Mitochondrial membrane potential
  • SDHA
  • TMRM

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells. / Morganti, Claudia; Bonora, Massimo; Ito, Kyoko; Ito, Keisuke.

In: Stem Cell Research, Vol. 40, 101573, 01.10.2019.

Research output: Contribution to journalArticle

@article{2e555ac6030b481db822096397acfc66,
title = "Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells",
abstract = "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.",
keywords = "ATP synthase, Electron transport chain, HSC, Mitochondrial membrane potential, SDHA, TMRM",
author = "Claudia Morganti and Massimo Bonora and Kyoko Ito and Keisuke Ito",
year = "2019",
month = "10",
day = "1",
doi = "10.1016/j.scr.2019.101573",
language = "English (US)",
volume = "40",
journal = "Stem Cell Research",
issn = "1873-5061",
publisher = "Elsevier",

}

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

PY - 2019/10/1

Y1 - 2019/10/1

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

VL - 40

JO - Stem Cell Research

JF - Stem Cell Research

SN - 1873-5061

M1 - 101573

ER -