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 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 and Lykke Sylow ()
Additional contact information
Tang Cam Phung Pham: University of Copenhagen
Steffen Henning Raun: University of Copenhagen
Essi Havula: University of Helsinki
Carlos Henriquez-Olguín: University of Copenhagen
Diana Rubalcava-Gracia: Karolinska Institutet
Emma Frank: University of Copenhagen
Andreas Mæchel Fritzen: University of Copenhagen
Paulo R. Jannig: Karolinska Institutet
Nicoline Resen Andersen: University of Copenhagen
Rikke Kruse: Odense University Hospital
Mona Sadek Ali: University of Copenhagen
Andrea Irazoki: University of Copenhagen
Jens Frey Halling: University of Copenhagen
Stine Ringholm: University of Copenhagen
Elise J. Needham: University of Sydney
Solvejg Hansen: University of Copenhagen
Anders Krogh Lemminger: University of Copenhagen
Peter Schjerling: Bispebjerg Hospital
Maria Houborg Petersen: Odense University Hospital
Martin Eisemann Almeida: Odense University Hospital
Thomas Elbenhardt Jensen: University of Copenhagen
Bente Kiens: University of Copenhagen
Morten Hostrup: University of Copenhagen
Steen Larsen: University of Copenhagen
Niels Ørtenblad: University of Southern Denmark
Kurt Højlund: Odense University Hospital
Michael Kjær: Bispebjerg Hospital
Jorge L. Ruas: Karolinska Institutet
Aleksandra Trifunovic: University of Cologne
Jørgen Frank Pind Wojtaszewski: University of Copenhagen
Joachim Nielsen: University of Southern Denmark
Klaus Qvortrup: University of Copenhagen
Henriette Pilegaard: University of Copenhagen
Erik Arne Richter: University of Copenhagen
Lykke Sylow: University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-54183-4

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