| Title: |
Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart |
| Authors: |
Milenkovic, I.; Santos Vieira, H.G.; Lucas, M.C.; Ruiz-Orera, J.; Patone, G.; Kesteven, S.; Wu, J.; Feneley, M.; Espadas, G.; Sabidó, E.; Hübner, N.; van Heesch, S.; Völkers, M.; Novoa, E.M. |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2023 |
| Collection: |
Max-Delbrueck-Center for Molecular Medicine, Berlin: MDC Repository |
| Subject Terms: |
Cardiovascular and Metabolic Diseases; Topic 1: Genes; Cells and Cell-Based Medicine |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf; other |
| Language: |
English |
| Relation: |
https://edoc.mdc-berlin.de/id/eprint/23188/1/23188oa.pdf; https://edoc.mdc-berlin.de/id/eprint/23188/2/23188suppl.zip; Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart. Milenkovic, I., Santos Vieira, H.G., Lucas, M.C., Ruiz-Orera, J., Patone, G., Kesteven, S., Wu, J., Feneley, M., Espadas, G., Sabidó, E., Hübner, N., van Heesch, S., Völkers, M. and Novoa, E.M. Nucleic Acids Research 51 (11): 5301-5324. 23 June 2023; PMID:36882085; https://doi.org/10.1093/nar/gkad121 |
| DOI: |
10.1093/nar/gkad121 |
| Availability: |
https://edoc.mdc-berlin.de/id/eprint/23188/; https://edoc.mdc-berlin.de/23188/; https://doi.org/10.1093/nar/gkad121 |
| Rights: |
cc_by_nc_4 |
| Accession Number: |
edsbas.CB9424E5 |
| Database: |
BASE |