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.; Novoa, E.M.

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., 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.
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
ISSN:	0305-1048
Publisher:	Oxford University Press
Volume:	51
Number:	11
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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