1. Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
- Author
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Hubert Rehrauer, Margarita Brilkova, Erik C. Böttger, Reda Juskeviciene, Dimitri Shcherbakov, Adrián Cortés Sanchón, Endre Laczko, and University of Zurich
- Subjects
Ribosomal Proteins ,Mitochondrial DNA ,misreading ,Aging ,Mutant ,Citric Acid Cycle ,Mutation, Missense ,610 Medicine & health ,Mice, Transgenic ,Oxidative phosphorylation ,Biology ,Mitochondrion ,medicine.disease_cause ,Catalysis ,Article ,Inorganic Chemistry ,lcsh:Chemistry ,Mitochondrial Proteins ,Mice ,Adenosine Triphosphate ,Downregulation and upregulation ,medicine ,Animals ,Gene Knock-In Techniques ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Mutation ,10179 Institute of Medical Microbiology ,Organic Chemistry ,Brain ,General Medicine ,Mitochondria ,Misreading ,Metabolome ,Phenotype ,Computer Science Applications ,Cell biology ,Citric acid cycle ,lcsh:Biology (General) ,lcsh:QD1-999 ,Gene Expression Regulation ,Protein Biosynthesis ,570 Life sciences ,biology ,metabolome - Abstract
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 Mrps5V338Y/V338Y 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)., International Journal of Molecular Sciences, 22 (5), ISSN:1422-0067
- Published
- 2021