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Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart

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Item Type:Article
Title:Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart
Creators Name:Milenkovic, I. and Santos Vieira, H.G. and Lucas, M.C. and Ruiz-Orera, J. and Patone, G. and Kesteven, S. and Wu, J. and Feneley, M. and Espadas, G. and Sabidó, E. and Hübner, N. and van Heesch, S. and Völkers, M. and Novoa, E.M.
Abstract:The existence of naturally occurring ribosome heterogeneity is now a well-acknowledged phenomenon. However, whether this heterogeneity leads to functionally diverse 'specialized ribosomes' is still a controversial topic. Here, we explore the biological function of RPL3L (uL3L), a ribosomal protein (RP) paralogue of RPL3 (uL3) that is exclusively expressed in skeletal muscle and heart tissues, by generating a viable homozygous Rpl3l knockout mouse strain. We identify a rescue mechanism in which, upon RPL3L depletion, RPL3 becomes up-regulated, yielding RPL3-containing ribosomes instead of RPL3L-containing ribosomes that are typically found in cardiomyocytes. Using both ribosome profiling (Ribo-seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L modulates neither translational efficiency nor ribosome affinity towards a specific subset of transcripts. In contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of fine-tuning of mitochondrial activity. Our results demonstrate that the existence of tissue-specific RP paralogues does not necessarily lead to enhanced translation of specific transcripts or modulation of translational output. Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity.
Keywords:Heart, Mammals, Mitochondria, Skeletal Muscle, Protein Biosynthesis, Ribosomal Proteins, Ribosomes, Animals, Mice
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:5301-5324
Date:23 June 2023
Official Publication:https://doi.org/10.1093/nar/gkad121
PubMed:View item in PubMed

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