Nature Communications (Nov 2024)
The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms
- Tang Cam Phung Pham,
- Steffen Henning Raun,
- Essi Havula,
- Carlos Henriquez-Olguín,
- Diana Rubalcava-Gracia,
- Emma Frank,
- Andreas Mæchel Fritzen,
- Paulo R. Jannig,
- Nicoline Resen Andersen,
- Rikke Kruse,
- Mona Sadek Ali,
- Andrea Irazoki,
- Jens Frey Halling,
- Stine Ringholm,
- Elise J. Needham,
- Solvejg Hansen,
- Anders Krogh Lemminger,
- Peter Schjerling,
- Maria Houborg Petersen,
- Martin Eisemann de Almeida,
- Thomas Elbenhardt Jensen,
- Bente Kiens,
- Morten Hostrup,
- Steen Larsen,
- Niels Ørtenblad,
- Kurt Højlund,
- Michael Kjær,
- Jorge L. Ruas,
- Aleksandra Trifunovic,
- Jørgen Frank Pind Wojtaszewski,
- Joachim Nielsen,
- Klaus Qvortrup,
- Henriette Pilegaard,
- Erik Arne Richter,
- Lykke Sylow
Affiliations
- Tang Cam Phung Pham
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Steffen Henning Raun
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Essi Havula
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki
- Carlos Henriquez-Olguín
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Diana Rubalcava-Gracia
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- Emma Frank
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Andreas Mæchel Fritzen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Paulo R. Jannig
- Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet
- Nicoline Resen Andersen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Rikke Kruse
- Steno Diabetes Center Odense, Odense University Hospital
- Mona Sadek Ali
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Andrea Irazoki
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Jens Frey Halling
- Department of Biology, University of Copenhagen
- Stine Ringholm
- Department of Biology, University of Copenhagen
- Elise J. Needham
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney
- Solvejg Hansen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Anders Krogh Lemminger
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital
- Maria Houborg Petersen
- Steno Diabetes Center Odense, Odense University Hospital
- Martin Eisemann de Almeida
- Steno Diabetes Center Odense, Odense University Hospital
- Thomas Elbenhardt Jensen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Bente Kiens
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Morten Hostrup
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Steen Larsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Niels Ørtenblad
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark
- Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital
- Michael Kjær
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital
- Jorge L. Ruas
- Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet
- Aleksandra Trifunovic
- Institute for Mitochondrial Diseases and Aging, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne
- Jørgen Frank Pind Wojtaszewski
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Joachim Nielsen
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark
- Klaus Qvortrup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
- Henriette Pilegaard
- Department of Biology, University of Copenhagen
- Erik Arne Richter
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- Lykke Sylow
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
- DOI
- https://doi.org/10.1038/s41467-024-54183-4
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
Abstract 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.
