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Title: HtrA2 deficiency causes mitochondrial uncoupling through the F₁F₀-ATP synthase and consequent ATP depletion.
Authors: Plun-Favreau, H.
Burchell, V.S.
Holmström, K.M.
Yao, Z.
Deas, E.
Cain, K.
Fedele, V.
Moisoi, Nicoleta
Campanella, M.
Miguel Martins, L.
Wood, N.W.
Gourine, A.V.
Abramov, A.Y.
First Published: 16-May-2012
Publisher: Nature Publishing Group for Associazione Differenziamento e Morte Cellulare
Citation: Cell Death and Disease, 2012, 3, e335
Abstract: Loss of the mitochondrial protease HtrA2 (Omi) in mice leads to mitochondrial dysfunction, neurodegeneration and premature death, but the mechanism underlying this pathology remains unclear. Using primary cultures from wild-type and HtrA2-knockout mice, we find that HtrA2 deficiency significantly reduces mitochondrial membrane potential in a range of cell types. This depolarisation was found to result from mitochondrial uncoupling, as mitochondrial respiration was increased in HtrA2-deficient cells and respiratory control ratio was dramatically reduced. HtrA2-knockout cells exhibit increased proton translocation through the ATP synthase, in combination with decreased ATP production and truncation of the F1 α-subunit, suggesting the ATP synthase as the source of the proton leak. Uncoupling in the HtrA2-deficient mice is accompanied by altered breathing pattern and, on a cellular level, ATP depletion and vulnerability to chemical ischaemia. We propose that this vulnerability may ultimately cause the neurodegeneration observed in these mice.
DOI Link: 10.1038/cddis.2012.77
eISSN: 2041-4889
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2012, Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit
Description: PMCID: PMC3388244
Appears in Collections:Published Articles, MRC Toxicology Unit

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