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Zhang, Peixiang; Verity, M. Anthony; Reue, Karen
Cell metabolism, 08/2014, Letnik: 20, Številka: 2Journal Article
LPIN1 encodes lipin-1, a phosphatidic acid phosphatase (PAP) enzyme that catalyzes the dephosphorylation of phosphatidic acid to form diacylglycerol. Homozygous LPIN1 gene mutations cause severe rhabdomyolysis, and heterozygous LPIN1 missense mutations may promote statin-induced myopathy. We demonstrate that lipin-1–related myopathy in the mouse is associated with a blockade in autophagic flux and accumulation of aberrant mitochondria. Lipin-1 PAP activity is required for maturation of autolysosomes, through its activation of the protein kinase D (PKD)-Vps34 phosphatidylinositol 3-kinase signaling cascade. Statin treatment also reduces PKD activation and autophagic flux, which are compounded by diminished mammalian target of rapamycin (mTOR) abundance in lipin-1-haploinsufficent and -deficient muscle. Lipin-1 restoration in skeletal muscle prevents myonecrosis and statin toxicity in vivo, and activated PKD rescues autophagic flux in lipin-1-deficient cells. Our findings identify lipin-1 PAP activity as a component of the macroautophagy pathway and define the basis for lipin-1-related myopathies. Display omitted •Lipin-1 deficiency causes muscle damage related to impaired autophagy clearance•Lipin-1 phosphatidate phosphatase activity promotes autolysosome maturation•Autophagy flux in lipin-1-deficient cells is rescued by activated protein kinase D•Lipin-1 and statin drug effects converge in the autophagy pathway in muscle Lipin-1 mutations in humans are associated with muscular disorders, including rhabdomyolysis and statin-induced myopathies. Zhang et al. show that lipin-1 generates the second messenger diacylglycerol, which promotes PI3K signaling and autophagy, counteracting statin-induced decrease in skeletal muscle autophagy. Lipin-1 restoration in skeletal muscle prevents statin toxicity.
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