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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6678443 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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