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

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  • dc.contributor.author Milenkovic, Ivan
  • dc.contributor.author Santos Vieira, Helaine Graziele
  • dc.contributor.author Lucas, Morghan C.
  • dc.contributor.author Ruiz-Orera, Jorge
  • dc.contributor.author Patone, Giannino
  • dc.contributor.author Kesteven, Scott
  • dc.contributor.author Wu, Jianxin
  • dc.contributor.author Feneley, Michael
  • dc.contributor.author Espadas, Guadalupe
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Hübner, Norbert
  • dc.contributor.author van Heesch, Sebastiaan
  • dc.contributor.author Völkers, Mirko
  • dc.contributor.author Novoa, Eva Maria
  • dc.date.accessioned 2023-09-26T06:30:54Z
  • dc.date.available 2023-09-26T06:30:54Z
  • dc.date.issued 2023
  • dc.description.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.
  • dc.description.sponsorship The European Union's Horizon 2020 Research and Innovation Program under the Marie Skodowska-Curie grant agreement [713673]; the Australian Research Council [DE170100506 to E.M.N.]; the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) [PGC2018-098152-A-100 to E.M.N.]; the European Union Horizon 2020 Research and Innovation Program ERC advanced grant [AdG788970 to N.H.] and ERC starting grant [StG101042103 to E.M.N.]; the Leducq Foundation [16CVD03 to N.H.]; the Chan Zuckerberg Foundation [2019-20266 to N.H.]; and ‘la Caixa’ INPhINIT PhD fellowship [LCF/BQ/DI18/11660028 to I.M.]. We acknowledge the support of the MEIC to the EMBL partnership, Centro de Excelencia Severo Ochoa and CERCA Programme/Generalitat de Catalunya. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. Conflict of interest statement. E.M.N. has received travel expenses from ONT to participate in nanopore conferences. I.M. has received a travel bursary from ONT to present his work in international conferences. E.M.N. is Scientific Advisory Board member for IMMAGINA Biotech. The authors declare that they have no competing interests.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Milenkovic I, Santos Vieira HG, Lucas MC, Ruiz-Orera J, Patone G, Kesteven S, Wu J, Feneley M, Espadas G, Sabidó E, Hübner N, van Heesch S, Völkers M, Novoa EM. Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart. Nucleic Acids Res. 2023;51(11):5301-24. DOI: 10.1093/nar/gkad121
  • dc.identifier.doi http://dx.doi.org/10.1093/nar/gkad121
  • dc.identifier.issn 0305-1048
  • dc.identifier.uri http://hdl.handle.net/10230/57950
  • dc.language.iso eng
  • dc.publisher Oxford University Press
  • dc.relation.ispartof Nucleic Acids Res. 2023;51(11):5301-24
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/713673
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-098152-A-100
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/788970
  • dc.rights © The Author(s) 2023. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
  • dc.title Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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