Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5<sup>V338Y/V338Y</sup> mice show decreased oxygen consumption and reduced ATP levels. Us...

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Main Authors:	Dimitri Shcherbakov, Reda Juskeviciene, Adrián Cortés Sanchón, Margarita Brilkova, Hubert Rehrauer, Endre Laczko, Erik C. Böttger
Format:	Article
Language:	English
Published:	MDPI AG 2021-03-01
Series:	International Journal of Molecular Sciences
Subjects:	mitochondria misreading brain aging metabolome
Online Access:	https://www.mdpi.com/1422-0067/22/5/2746

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record_format	Article
spelling	doaj-b6f327e57cbb40ad89d00f7823c5124a2021-03-10T00:00:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01222746274610.3390/ijms22052746Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene ExpressionDimitri Shcherbakov0Reda Juskeviciene1Adrián Cortés Sanchón2Margarita Brilkova3Hubert Rehrauer4Endre Laczko5Erik C. Böttger6Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, SwitzerlandInstitut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, SwitzerlandInstitut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, SwitzerlandInstitut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, SwitzerlandFunctional Genomics Center Zurich, ETH Zürich und Universität Zürich, 8006 Zürich, SwitzerlandFunctional Genomics Center Zurich, ETH Zürich und Universität Zürich, 8006 Zürich, SwitzerlandInstitut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, SwitzerlandMitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5<sup>V338Y/V338Y</sup> mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).https://www.mdpi.com/1422-0067/22/5/2746mitochondriamisreadingbrainagingmetabolome
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Dimitri Shcherbakov Reda Juskeviciene Adrián Cortés Sanchón Margarita Brilkova Hubert Rehrauer Endre Laczko Erik C. Böttger
spellingShingle	Dimitri Shcherbakov Reda Juskeviciene Adrián Cortés Sanchón Margarita Brilkova Hubert Rehrauer Endre Laczko Erik C. Böttger Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression International Journal of Molecular Sciences mitochondria misreading brain aging metabolome
author_facet	Dimitri Shcherbakov Reda Juskeviciene Adrián Cortés Sanchón Margarita Brilkova Hubert Rehrauer Endre Laczko Erik C. Böttger
author_sort	Dimitri Shcherbakov
title	Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
title_short	Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
title_full	Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
title_fullStr	Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
title_full_unstemmed	Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
title_sort	mitochondrial mistranslation in brain provokes a metabolic response which mitigates the age-associated decline in mitochondrial gene expression
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2021-03-01
description	Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5<sup>V338Y/V338Y</sup> mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).
topic	mitochondria misreading brain aging metabolome
url	https://www.mdpi.com/1422-0067/22/5/2746
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Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

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