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EMBO Rep. 2018 Nov;19(11). pii: e46193. doi: 10.15252/embr.201846193. Epub 2018 Sep 20.

Mutant MRPS5 affects mitoribosomal accuracy and confers stress-related behavioral alterations.

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Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
Anatomisches Institut, Universität Zürich, Zürich, Switzerland.
Institut für Bewegungswissenschaften und Sport, ETH Zürich, Zürich, Switzerland.
Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
Transfaculty Research Platform Molecular and Cognitive Neurosciences, Universitäre Psychiatrische Kliniken Basel, Basel, Switzerland.
GenOway, Lyon Cedex 07, France.
Neuro- und Ophthalmopathologie, Universitätsspital Basel, Basel, Switzerland.
Functional Genomics Center Zurich, ETH Zürich und Universität Zürich, Zürich, Switzerland.
Institut de biologie moléculaire et cellulaire du CNRS, Université de Strasbourg, Strasbourg, France.
Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland


The 1555 A to G substitution in mitochondrial 12S A-site rRNA is associated with maternally transmitted deafness of variable penetrance in the absence of otherwise overt disease. Here, we recapitulate the suggested A1555G-mediated pathomechanism in an experimental model of mitoribosomal mistranslation by directed mutagenesis of mitoribosomal protein MRPS5. We first establish that the ratio of cysteine/methionine incorporation and read-through of mtDNA-encoded MT-CO1 protein constitute reliable measures of mitoribosomal misreading. Next, we demonstrate that human HEK293 cells expressing mutant V336Y MRPS5 show increased mitoribosomal mistranslation. As for immortalized lymphocytes of individuals with the pathogenic A1555G mutation, we find little changes in the transcriptome of mutant V336Y MRPS5 HEK cells, except for a coordinated upregulation of transcripts for cytoplasmic ribosomal proteins. Homozygous knock-in mutant Mrps5 V338Y mice show impaired mitochondrial function and a phenotype composed of enhanced susceptibility to noise-induced hearing damage and anxiety-related behavioral alterations. The experimental data in V338Y mutant mice point to a key role of mitochondrial translation and function in stress-related behavioral and physiological adaptations.


aging; disease; misreading; mitochondria; protein synthesis

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