Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

Robert D. Guzy; Beatrice Hoyos; Emmanuel Robin; Hong Chen; Liping Liu; Kyle D. Mansfield; M. Celeste Simon; Ulrich Hammerling; Paul T. Schumacker

doi:10.1016/j.cmet.2005.05.001

Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

Robert D. Guzy, Beatrice Hoyos, Emmanuel Robin, Hong Chen, Liping Liu, Kyle D. Mansfield, M. Celeste Simon, Ulrich Hammerling, Paul T. Schumacker^*

^*Corresponding author for this work

Pediatrics

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Abstract

Multicellular organisms initiate adaptive responses when oxygen (O₂) availability decreases, but the underlying mechanism of O₂ sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α and that an increase in reactive oxygen species (ROS) links this complex to HIF-α stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1α stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O₂ sensors and signal hypoxic HIF-1α and HIF-2α stabilization by releasing ROS to the cytosol.

Original language	English (US)
Pages (from-to)	401-408
Number of pages	8
Journal	Cell Metabolism
Volume	1
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2005.05.001
State	Published - Jun 2005

ASJC Scopus subject areas

Molecular Biology
Physiology
Cell Biology

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@article{80949032481c456fb897a718802bd269,

title = "Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing",

abstract = "Multicellular organisms initiate adaptive responses when oxygen (O2) availability decreases, but the underlying mechanism of O2 sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α and that an increase in reactive oxygen species (ROS) links this complex to HIF-α stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1α stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIF-1α and HIF-2α stabilization by releasing ROS to the cytosol.",

author = "Guzy, {Robert D.} and Beatrice Hoyos and Emmanuel Robin and Hong Chen and Liping Liu and Mansfield, {Kyle D.} and Simon, {M. Celeste} and Ulrich Hammerling and Schumacker, {Paul T.}",

note = "Funding Information: We thank Matthew Mack for review of this manuscript. Funding and support was provided by the Medical Scientist Training Program (R.D.G.), American Heart Association (K.D.M.), Howard Hughes Medical Institute (L.L. and M.C.S.), and NIH (M.C.S.: 66310, P.T.S.: HL66315, HL35440). ",

year = "2005",

month = jun,

doi = "10.1016/j.cmet.2005.05.001",

language = "English (US)",

volume = "1",

pages = "401--408",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "6",

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TY - JOUR

T1 - Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

AU - Guzy, Robert D.

AU - Hoyos, Beatrice

AU - Robin, Emmanuel

AU - Chen, Hong

AU - Liu, Liping

AU - Mansfield, Kyle D.

AU - Simon, M. Celeste

AU - Hammerling, Ulrich

AU - Schumacker, Paul T.

N1 - Funding Information: We thank Matthew Mack for review of this manuscript. Funding and support was provided by the Medical Scientist Training Program (R.D.G.), American Heart Association (K.D.M.), Howard Hughes Medical Institute (L.L. and M.C.S.), and NIH (M.C.S.: 66310, P.T.S.: HL66315, HL35440).

PY - 2005/6

Y1 - 2005/6

N2 - Multicellular organisms initiate adaptive responses when oxygen (O2) availability decreases, but the underlying mechanism of O2 sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α and that an increase in reactive oxygen species (ROS) links this complex to HIF-α stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1α stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIF-1α and HIF-2α stabilization by releasing ROS to the cytosol.

AB - Multicellular organisms initiate adaptive responses when oxygen (O2) availability decreases, but the underlying mechanism of O2 sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α and that an increase in reactive oxygen species (ROS) links this complex to HIF-α stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1α stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIF-1α and HIF-2α stabilization by releasing ROS to the cytosol.

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U2 - 10.1016/j.cmet.2005.05.001

DO - 10.1016/j.cmet.2005.05.001

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AN - SCOPUS:24144493814

SN - 1550-4131

VL - 1

SP - 401

EP - 408

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

Abstract

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