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Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

How does a single amino acid mutation occurring in the blinding disease, Leber’s hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free En...

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Autores principales: Fuller, Jack T., Barnes, Steven, Sadun, Lorenzo A., Ajmera, Pujan, Alexandrova, Anastassia N., Sadun, Alfredo A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523484/
https://www.ncbi.nlm.nih.gov/pubmed/37733737
http://dx.doi.org/10.1073/pnas.2304884120
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author Fuller, Jack T.
Barnes, Steven
Sadun, Lorenzo A.
Ajmera, Pujan
Alexandrova, Anastassia N.
Sadun, Alfredo A.
author_facet Fuller, Jack T.
Barnes, Steven
Sadun, Lorenzo A.
Ajmera, Pujan
Alexandrova, Anastassia N.
Sadun, Alfredo A.
author_sort Fuller, Jack T.
collection PubMed
description How does a single amino acid mutation occurring in the blinding disease, Leber’s hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation’s replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
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spelling pubmed-105234842023-09-28 Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy Fuller, Jack T. Barnes, Steven Sadun, Lorenzo A. Ajmera, Pujan Alexandrova, Anastassia N. Sadun, Alfredo A. Proc Natl Acad Sci U S A Physical Sciences How does a single amino acid mutation occurring in the blinding disease, Leber’s hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation’s replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy. National Academy of Sciences 2023-09-21 2023-09-26 /pmc/articles/PMC10523484/ /pubmed/37733737 http://dx.doi.org/10.1073/pnas.2304884120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Physical Sciences
Fuller, Jack T.
Barnes, Steven
Sadun, Lorenzo A.
Ajmera, Pujan
Alexandrova, Anastassia N.
Sadun, Alfredo A.
Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title_full Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title_fullStr Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title_full_unstemmed Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title_short Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy
title_sort coenzyme q10 trapping in mitochondrial complex i underlies leber’s hereditary optic neuropathy
topic Physical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523484/
https://www.ncbi.nlm.nih.gov/pubmed/37733737
http://dx.doi.org/10.1073/pnas.2304884120
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