title: HtrA2 deficiency causes mitochondrial uncoupling through the F₁F₀-ATP synthase and consequent ATP depletion.
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.
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. h.plun-favreau@ion.ucl.ac.uk
authors: H
authors: H
authors: Plun-Favreau
authors: V S
authors: VS
authors: Burchell
authors: K M
authors: KM
authors: Holmström
authors: Z
authors: Z
authors: Yao
authors: E
authors: E
authors: Deas
authors: K
authors: K
authors: Cain
authors: V
authors: V
authors: Fedele
authors: N
authors: N
authors: Moisoi
authors: M
authors: M
authors: Campanella
authors: L
authors: L
authors: Miguel Martins
authors: N W
authors: NW
authors: Wood
authors: A V
authors: AV
authors: Gourine
authors: A Y
authors: AY
authors: Abramov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019069:Cell Respiration; D000074923:High-Temperature Requirement A Serine Peptidase 2; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010085:Oxidative Phosphorylation; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D006180:Proton-Translocating ATPases