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Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan

Mitochondrial complex I—the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery—has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitocho...

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Autores principales: Hirose, Misa, Schilf, Paul, Zarse, Kim, Busch, Hauke, Fuellen, Georg, Jöhren, Olaf, Köhling, Rüdiger, König, Inke R., Richer, Barbara, Rupp, Jan, Schwaninger, Markus, Seeger, Karsten, Sina, Christian, Ristow, Michael, Ibrahim, Saleh M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678443/
https://www.ncbi.nlm.nih.gov/pubmed/31337008
http://dx.doi.org/10.3390/genes10070532
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author Hirose, Misa
Schilf, Paul
Zarse, Kim
Busch, Hauke
Fuellen, Georg
Jöhren, Olaf
Köhling, Rüdiger
König, Inke R.
Richer, Barbara
Rupp, Jan
Schwaninger, Markus
Seeger, Karsten
Sina, Christian
Ristow, Michael
Ibrahim, Saleh M.
author_facet Hirose, Misa
Schilf, Paul
Zarse, Kim
Busch, Hauke
Fuellen, Georg
Jöhren, Olaf
Köhling, Rüdiger
König, Inke R.
Richer, Barbara
Rupp, Jan
Schwaninger, Markus
Seeger, Karsten
Sina, Christian
Ristow, Michael
Ibrahim, Saleh M.
author_sort Hirose, Misa
collection PubMed
description Mitochondrial complex I—the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery—has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in mt-Nd2 lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.
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spelling pubmed-66784432019-08-19 Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan Hirose, Misa Schilf, Paul Zarse, Kim Busch, Hauke Fuellen, Georg Jöhren, Olaf Köhling, Rüdiger König, Inke R. Richer, Barbara Rupp, Jan Schwaninger, Markus Seeger, Karsten Sina, Christian Ristow, Michael Ibrahim, Saleh M. Genes (Basel) Article Mitochondrial complex I—the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery—has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in mt-Nd2 lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases. MDPI 2019-07-13 /pmc/articles/PMC6678443/ /pubmed/31337008 http://dx.doi.org/10.3390/genes10070532 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hirose, Misa
Schilf, Paul
Zarse, Kim
Busch, Hauke
Fuellen, Georg
Jöhren, Olaf
Köhling, Rüdiger
König, Inke R.
Richer, Barbara
Rupp, Jan
Schwaninger, Markus
Seeger, Karsten
Sina, Christian
Ristow, Michael
Ibrahim, Saleh M.
Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title_full Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title_fullStr Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title_full_unstemmed Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title_short Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
title_sort maternally inherited differences within mitochondrial complex i control murine healthspan
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678443/
https://www.ncbi.nlm.nih.gov/pubmed/31337008
http://dx.doi.org/10.3390/genes10070532
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