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Phenotype of Mrps5-Associated Phylogenetic Polymorphisms Is Intimately Linked to Mitoribosomal Misreading


Juskeviciene, Reda; Fritz, Ann-Kristina; Brilkova, Margarita; Akbergenov, Rashid; Schmitt, Karen; Rehrauer, Hubert; Laczko, Endre; Isnard-Petit, Patricia; Thiam, Kader; Eckert, Anne; Schacht, Jochen; Wolfer, David P; Böttger, Erik C; Shcherbakov, Dimitri (2022). Phenotype of Mrps5-Associated Phylogenetic Polymorphisms Is Intimately Linked to Mitoribosomal Misreading. International Journal of Molecular Sciences, 23(8):4384.

Abstract

We have recently identified point mutation V336Y in mitoribosomal protein Mrps5 (uS5m) as a mitoribosomal ram (ribosomal ambiguity) mutation conferring error-prone mitochondrial protein synthesis. In vivo in transgenic knock-in animals, homologous mutation V338Y was associated with a discrete phenotype including impaired mitochondrial function, anxiety-related behavioral alterations, enhanced susceptibility to noise-induced hearing damage, and accelerated metabolic aging in muscle. To challenge the postulated link between Mrps5 V338Y-mediated misreading and the in vivo phenotype, we introduced mutation G315R into the mouse Mrps5 gene as Mrps5 G315R is homologous to the established bacterial ram mutation RpsE (uS5) G104R. However, in contrast to bacterial translation, the homologous G → R mutation in mitoribosomal Mrps5 did not affect the accuracy of mitochondrial protein synthesis. Importantly, in the absence of mitochondrial misreading, homozygous mutant MrpS5$^{G315R/G315R}$ mice did not show a phenotype distinct from wild-type animals.

Abstract

We have recently identified point mutation V336Y in mitoribosomal protein Mrps5 (uS5m) as a mitoribosomal ram (ribosomal ambiguity) mutation conferring error-prone mitochondrial protein synthesis. In vivo in transgenic knock-in animals, homologous mutation V338Y was associated with a discrete phenotype including impaired mitochondrial function, anxiety-related behavioral alterations, enhanced susceptibility to noise-induced hearing damage, and accelerated metabolic aging in muscle. To challenge the postulated link between Mrps5 V338Y-mediated misreading and the in vivo phenotype, we introduced mutation G315R into the mouse Mrps5 gene as Mrps5 G315R is homologous to the established bacterial ram mutation RpsE (uS5) G104R. However, in contrast to bacterial translation, the homologous G → R mutation in mitoribosomal Mrps5 did not affect the accuracy of mitochondrial protein synthesis. Importantly, in the absence of mitochondrial misreading, homozygous mutant MrpS5$^{G315R/G315R}$ mice did not show a phenotype distinct from wild-type animals.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > Institute of Medical Microbiology
04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > Catalysis
Life Sciences > Molecular Biology
Physical Sciences > Spectroscopy
Physical Sciences > Computer Science Applications
Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Organic Chemistry
Physical Sciences > Inorganic Chemistry
Language:English
Date:15 April 2022
Deposited On:02 Jun 2022 12:54
Last Modified:29 Jan 2024 02:40
Publisher:MDPI Publishing
ISSN:1422-0067
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.3390/ijms23084384
PubMed ID:35457201
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)