HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion

H. Plun-Favreau, V. S. Burchell, K. M. Holmström, Z. Yao, E. Deas, K. Cain, V. Fedele, N. Moisoi, M. Campanella, L. Miguel Martins, N. W. Wood, A. V. Gourine, A. Y. Abramov

Research output: Contribution to journalArticle

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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 a-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.

Original languageEnglish
JournalCell Death and Disease
Volume3
Issue number6
DOIs
Publication statusPublished - Jun 2012

Fingerprint

Adenosine Triphosphate
Protons
Respiration
Premature Mortality
Mitochondrial Membrane Potential
Knockout Mice
Peptide Hydrolases
Ischemia
Pathology

Keywords

  • ATP synthase
  • HtrA2
  • mitochondria
  • uncoupling

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Plun-Favreau, H., Burchell, V. S., Holmström, K. M., Yao, Z., Deas, E., Cain, K., ... Abramov, A. Y. (2012). HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion. Cell Death and Disease, 3(6). https://doi.org/10.1038/cddis.2012.77

HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion. / Plun-Favreau, H.; Burchell, V. S.; Holmström, K. M.; Yao, Z.; Deas, E.; Cain, K.; Fedele, V.; Moisoi, N.; Campanella, M.; Martins, L. Miguel; Wood, N. W.; Gourine, A. V.; Abramov, A. Y.

In: Cell Death and Disease, Vol. 3, No. 6, 06.2012.

Research output: Contribution to journalArticle

Plun-Favreau, H, Burchell, VS, Holmström, KM, Yao, Z, Deas, E, Cain, K, Fedele, V, Moisoi, N, Campanella, M, Martins, LM, Wood, NW, Gourine, AV & Abramov, AY 2012, 'HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion', Cell Death and Disease, vol. 3, no. 6. https://doi.org/10.1038/cddis.2012.77
Plun-Favreau, H. ; Burchell, V. S. ; Holmström, K. M. ; Yao, Z. ; Deas, E. ; Cain, K. ; Fedele, V. ; Moisoi, N. ; Campanella, M. ; Martins, L. Miguel ; Wood, N. W. ; Gourine, A. V. ; Abramov, A. Y. / HtrA2 deficiency causes mitochondrial uncoupling through the F 1F0-ATP synthase and consequent ATP depletion. In: Cell Death and Disease. 2012 ; Vol. 3, No. 6.
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