Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I

Abstract NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction...

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Autores principales:	Franziska Nuber, Johannes Schimpf, Jean-Paul di Rago, Déborah Tribouillard-Tanvier, Vincent Procaccio, Marie-Laure Martin-Negrier, Aurélien Trimouille, Olivier Biner, Christoph von Ballmoos, Thorsten Friedrich
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/26652c8a0a244e3ead826a846ee6b58d
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spelling	oai:doaj.org-article:26652c8a0a244e3ead826a846ee6b58d2021-12-02T17:23:47ZBiochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I10.1038/s41598-021-91631-32045-2322https://doaj.org/article/26652c8a0a244e3ead826a846ee6b58d2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91631-3https://doaj.org/toc/2045-2322Abstract NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients’ tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.Franziska NuberJohannes SchimpfJean-Paul di RagoDéborah Tribouillard-TanvierVincent ProcaccioMarie-Laure Martin-NegrierAurélien TrimouilleOlivier BinerChristoph von BallmoosThorsten FriedrichNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Franziska Nuber Johannes Schimpf Jean-Paul di Rago Déborah Tribouillard-Tanvier Vincent Procaccio Marie-Laure Martin-Negrier Aurélien Trimouille Olivier Biner Christoph von Ballmoos Thorsten Friedrich Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
description	Abstract NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients’ tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.
format	article
author	Franziska Nuber Johannes Schimpf Jean-Paul di Rago Déborah Tribouillard-Tanvier Vincent Procaccio Marie-Laure Martin-Negrier Aurélien Trimouille Olivier Biner Christoph von Ballmoos Thorsten Friedrich
author_facet	Franziska Nuber Johannes Schimpf Jean-Paul di Rago Déborah Tribouillard-Tanvier Vincent Procaccio Marie-Laure Martin-Negrier Aurélien Trimouille Olivier Biner Christoph von Ballmoos Thorsten Friedrich
author_sort	Franziska Nuber
title	Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
title_short	Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
title_full	Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
title_fullStr	Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
title_full_unstemmed	Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I
title_sort	biochemical consequences of two clinically relevant nd-gene mutations in escherichia coli respiratory complex i
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/26652c8a0a244e3ead826a846ee6b58d
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_version_	1718380958647844864

Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I

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