The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms
Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.
Authors
- Aleksandra Trifunović (ORCID: https://orcid.org/0000-0002-5472-3517)
- Solvejg L. Hansen (ORCID: https://orcid.org/0000-0001-8127-2662)
- Anders Krogh Lemminger (ORCID: https://orcid.org/0000-0002-7929-7147)
- Essi Havula (ORCID: https://orcid.org/0000-0002-9253-5816)
- Elise J. Needham (ORCID: https://orcid.org/0000-0001-6326-9048)
- Andreas M. Fritzen (ORCID: https://orcid.org/0000-0001-8793-9739)
- Erik A. Richter (ORCID: https://orcid.org/0000-0002-6850-3056)
- Jorge L. Ruas (ORCID: https://orcid.org/0000-0002-1110-2606)
- Thomas E. Jensen (ORCID: https://orcid.org/0000-0001-6139-8268)
- Steffen H. Raun (ORCID: https://orcid.org/0000-0003-2050-505X)
- Stine Ringholm (ORCID: https://orcid.org/0000-0001-8436-559X)
- Tang Cam Phung Pham (ORCID: https://orcid.org/0000-0003-3476-6891)
- Henriette Pilegaard (ORCID: https://orcid.org/0000-0002-1071-0327)
- Kurt Højlund (ORCID: https://orcid.org/0000-0002-0891-4224)
- Jørgen F. P. Wojtaszewski (ORCID: https://orcid.org/0000-0001-8185-3408)
- Bente Kiens (ORCID: https://orcid.org/0000-0001-5705-5625)
- Jens Frey Halling (ORCID: https://orcid.org/0000-0002-8638-6746)
- Michael Kjær (ORCID: https://orcid.org/0000-0002-4582-8755)
- Steen Larsen (ORCID: https://orcid.org/0000-0002-5170-4337)
- Lykke Sylow (ORCID: https://orcid.org/0000-0003-0905-5932)
- Diana Rubalcava-Gracia (ORCID: https://orcid.org/0000-0002-4615-7375)
- Carlos Henríquez‐Olguín (ORCID: https://orcid.org/0000-0002-9315-9365)
- Peter Schjerling (ORCID: https://orcid.org/0000-0001-7138-3211)
- Joachim Nielsen (ORCID: https://orcid.org/0000-0003-1730-3094)
- Klaus Qvortrup (ORCID: https://orcid.org/0000-0001-8811-0260)
- Paulo R. Jannig
- Martin Eisemann de Almeida
- Emma Frank (ORCID: https://orcid.org/0000-0001-8065-2030)
- Nicoline R. Andersen (ORCID: https://orcid.org/0000-0002-1512-2727)
- Morten Hostrup (ORCID: https://orcid.org/0000-0002-6201-2483)
- Niels Ørtenblad (ORCID: https://orcid.org/0000-0001-9060-4139)
- Mona Sadek Ali (ORCID: https://orcid.org/0000-0003-1152-3256)
- Andrea Irazoki (ORCID: https://orcid.org/0000-0002-3118-3247)
- Maria Houborg Petersen
- Rikke Kruse
Institutions
- University of Copenhagen (DK)
- The University of Sydney (AU)
- University of Helsinki (FI)
- Steno Diabetes Centers (DK)
- Medical University of Białystok (PL)
- University of Southern Denmark (DK)
- University of Cologne (DE)
- Odense University Hospital (DK)
- Bispebjerg Hospital (DK)
- Karolinska Institutet (SE)
- Finis Terrae University (CL)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1038/s41467-024-54183-4
- Citations
- 13
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- European Commission
- University of Sydney
- Lundbeckfonden
- Novo Nordisk
- Danmarks Frie Forskningsfond
- Augustinus Fonden
- Faculty of Health and Medical Sciences, University of Western Australia
- Novo Nordisk Fonden
- Universitätsklinikum Köln
- H. Lundbeck A/S
- Bispebjerg Hospital
- Horizon 2020 Framework Programme
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet