Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL

Anthony E. Civitarese, Paul S. MacLean, Stacy Carling, Lyndal Kerr-Bayles, Ryan P. McMillan, Anson Pierce, Thomas C. Becker, Cedric Moro, Jean Finlayson, Natalie Lefort, Christopher B. Newgard, Lawrence Mandarino, William Cefalu, Ken Walder, Greg R. Collier, Matthew W. Hulver, Steven R. Smith, Eric Ravussin

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    Abstract

    Type 2 diabetes mellitus (T2DM) and aging are characterized by insulin resistance and impaired mitochondrial energetics. In lower organisms, remodeling by the protease pcp1 (PARL ortholog) maintains the function and lifecycle of mitochondria. We examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. PARL mRNA and mitochondrial mass were both reduced in elderly subjects and in subjects with T2DM. Muscle knockdown of PARL in mice resulted in malformed mitochondrial cristae, lower mitochondrial content, decreased PGC1α protein levels, and impaired insulin signaling. Suppression of PARL protein in healthy myotubes lowered mitochondrial mass and insulin-stimulated glycogen synthesis and increased reactive oxygen species production. We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM.

    Original languageEnglish (US)
    Pages (from-to)412-426
    Number of pages15
    JournalCell Metabolism
    Volume11
    Issue number5
    DOIs
    StatePublished - May 5 2010

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    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology

    Cite this

    Civitarese, A. E., MacLean, P. S., Carling, S., Kerr-Bayles, L., McMillan, R. P., Pierce, A., Becker, T. C., Moro, C., Finlayson, J., Lefort, N., Newgard, C. B., Mandarino, L., Cefalu, W., Walder, K., Collier, G. R., Hulver, M. W., Smith, S. R., & Ravussin, E. (2010). Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell Metabolism, 11(5), 412-426. https://doi.org/10.1016/j.cmet.2010.04.004