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Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae

The Drosophila bang-sensitive mutant tko(25t), manifesting a global deficiency in oxidative phosphorylation due to a mitochondrial protein synthesis defect, exhibits a pronounced delay in larval development. We previously identified a number of metabolic abnormalities in tko(25t) larvae, including e...

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Autores principales: George, Jack, Tuomela, Tea, Kemppainen, Esko, Nurminen, Antti, Braun, Samuel, Yalgin, Cagri, Jacobs, Howard T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988875/
https://www.ncbi.nlm.nih.gov/pubmed/31526131
http://dx.doi.org/10.1080/19336934.2019.1662266
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author George, Jack
Tuomela, Tea
Kemppainen, Esko
Nurminen, Antti
Braun, Samuel
Yalgin, Cagri
Jacobs, Howard T.
author_facet George, Jack
Tuomela, Tea
Kemppainen, Esko
Nurminen, Antti
Braun, Samuel
Yalgin, Cagri
Jacobs, Howard T.
author_sort George, Jack
collection PubMed
description The Drosophila bang-sensitive mutant tko(25t), manifesting a global deficiency in oxidative phosphorylation due to a mitochondrial protein synthesis defect, exhibits a pronounced delay in larval development. We previously identified a number of metabolic abnormalities in tko(25t) larvae, including elevated pyruvate and lactate, and found the larval gut to be a crucial tissue for the regulation of larval growth in the mutant. Here we established that expression of wild-type tko in any of several other tissues of tko(25t) also partially alleviates developmental delay. The effects appeared to be additive, whilst knockdown of tko in a variety of specific tissues phenocopied tko(25t), producing developmental delay and bang-sensitivity. These findings imply the existence of a systemic signal regulating growth in response to mitochondrial dysfunction. Drugs and RNAi-targeted on pyruvate metabolism interacted with tko(25t) in ways that implicated pyruvate or one of its metabolic derivatives in playing a central role in generating such a signal. RNA-seq revealed that dietary pyruvate-induced changes in transcript representation were mostly non-coherent with those produced by tko(25t) or high-sugar, consistent with the idea that growth regulation operates primarily at the translational and/or metabolic level.
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spelling pubmed-69888752020-02-14 Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae George, Jack Tuomela, Tea Kemppainen, Esko Nurminen, Antti Braun, Samuel Yalgin, Cagri Jacobs, Howard T. Fly (Austin) Research Paper The Drosophila bang-sensitive mutant tko(25t), manifesting a global deficiency in oxidative phosphorylation due to a mitochondrial protein synthesis defect, exhibits a pronounced delay in larval development. We previously identified a number of metabolic abnormalities in tko(25t) larvae, including elevated pyruvate and lactate, and found the larval gut to be a crucial tissue for the regulation of larval growth in the mutant. Here we established that expression of wild-type tko in any of several other tissues of tko(25t) also partially alleviates developmental delay. The effects appeared to be additive, whilst knockdown of tko in a variety of specific tissues phenocopied tko(25t), producing developmental delay and bang-sensitivity. These findings imply the existence of a systemic signal regulating growth in response to mitochondrial dysfunction. Drugs and RNAi-targeted on pyruvate metabolism interacted with tko(25t) in ways that implicated pyruvate or one of its metabolic derivatives in playing a central role in generating such a signal. RNA-seq revealed that dietary pyruvate-induced changes in transcript representation were mostly non-coherent with those produced by tko(25t) or high-sugar, consistent with the idea that growth regulation operates primarily at the translational and/or metabolic level. Taylor & Francis 2019-09-17 /pmc/articles/PMC6988875/ /pubmed/31526131 http://dx.doi.org/10.1080/19336934.2019.1662266 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper
George, Jack
Tuomela, Tea
Kemppainen, Esko
Nurminen, Antti
Braun, Samuel
Yalgin, Cagri
Jacobs, Howard T.
Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title_full Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title_fullStr Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title_full_unstemmed Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title_short Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae
title_sort mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in drosophila larvae
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988875/
https://www.ncbi.nlm.nih.gov/pubmed/31526131
http://dx.doi.org/10.1080/19336934.2019.1662266
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