Molecular basis of diseases caused by the mtDNA mutation m.8969G>A in the subunit a of ATP synthase
Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2018-08-01; 1859(8): 602-611
DOI: 10.1016/j.bbabio.2018.05.009
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1. Biochim Biophys Acta Bioenerg. 2018 Aug;1859(8):602-611. doi:
10.1016/j.bbabio.2018.05.009. Epub 2018 May 18.
Molecular basis of diseases caused by the mtDNA mutation m.8969G>A in the subunit
a of ATP synthase.
Skoczeń N(1), Dautant A(2), Binko K(1), Godard F(2), Bouhier M(2), Su X(3),
Lasserre JP(2), Giraud MF(2), Tribouillard-Tanvier D(2), Chen H(4), di Rago
JP(5), Kucharczyk R(6).
Author information:
(1)Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw,
Poland; CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077
Bordeaux, France.
(2)CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077
Bordeaux, France; Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux,
France.
(3)Nanjing University School of Medicine, Nanjing, Jiangsu, China; Center of Drug
Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical
University, Nanjing, Jiangsu, China.
(4)Nanjing University School of Medicine, Nanjing, Jiangsu, China.
(5)CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077
Bordeaux, France; Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux,
France. Electronic address: .
(6)Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw,
Poland. Electronic address: .
The ATP synthase which provides aerobic eukaryotes with ATP, organizes into a
membrane-extrinsic catalytic domain, where ATP is generated, and a
membrane-embedded FO domain that shuttles protons across the membrane. We
previously identified a mutation in the mitochondrial MT-ATP6 gene (m.8969G>A) in
a 14-year-old Chinese female who developed an isolated nephropathy followed by
brain and muscle problems. This mutation replaces a highly conserved serine
residue into asparagine at amino acid position 148 of the membrane-embedded
subunit a of ATP synthase. We showed that an equivalent of this mutation in yeast
(aS175N) prevents FO-mediated proton translocation. Herein we identified four
first-site intragenic suppressors (aN175D, aN175K, aN175I, and aN175T), which, in
light of a recently published atomic structure of yeast FO indicates that the
detrimental consequences of the original mutation result from the establishment
of hydrogen bonds between aN175 and a nearby glutamate residue (aE172) that was
proposed to be critical for the exit of protons from the ATP synthase towards the
mitochondrial matrix. Interestingly also, we found that the aS175N mutation can
be suppressed by second-site suppressors (aP12S, aI171F, aI171N, aI239F, and
aI200M), of which some are very distantly located (by 20-30 Å) from the original
mutation. The possibility to compensate through long-range effects the aS175N
mutation is an interesting observation that holds promise for the development of
therapeutic molecules.
Copyright © 2018 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbabio.2018.05.009
PMID: 29778688 [Indexed for MEDLINE]