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The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

Author

Listed:
  • Tang Cam Phung Pham

    (University of Copenhagen
    University of Copenhagen)

  • Steffen Henning Raun

    (University of Copenhagen)

  • Essi Havula

    (University of Helsinki)

  • Carlos Henriquez-Olguín

    (University of Copenhagen
    Universidad Finis Terrae)

  • Diana Rubalcava-Gracia

    (Karolinska Institutet)

  • Emma Frank

    (University of Copenhagen)

  • Andreas Mæchel Fritzen

    (University of Copenhagen
    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
    University of Copenhagen)

  • Maria Houborg Petersen

    (Odense University Hospital)

  • Martin Eisemann Almeida

    (Odense University Hospital
    University of Southern Denmark)

  • Thomas Elbenhardt Jensen

    (University of Copenhagen)

  • Bente Kiens

    (University of Copenhagen)

  • Morten Hostrup

    (University of Copenhagen)

  • Steen Larsen

    (University of Copenhagen
    Bispebjerg Hospital
    University of Copenhagen
    Medical University of Bialystok)

  • Niels Ørtenblad

    (University of Southern Denmark)

  • Kurt Højlund

    (Odense University Hospital
    University of Southern Denmark)

  • Michael Kjær

    (Bispebjerg Hospital
    University of Copenhagen)

  • 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
    University of Copenhagen)

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.

Suggested Citation

  • 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 Kr, 2024. "The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54183-4
    DOI: 10.1038/s41467-024-54183-4
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    References listed on IDEAS

    as
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    3. Riekelt H. Houtkooper & Laurent Mouchiroud & Dongryeol Ryu & Norman Moullan & Elena Katsyuba & Graham Knott & Robert W. Williams & Johan Auwerx, 2013. "Mitonuclear protein imbalance as a conserved longevity mechanism," Nature, Nature, vol. 497(7450), pages 451-457, May.
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