期刊
CELL METABOLISM
卷 20, 期 2, 页码 267-279出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.05.003
关键词
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资金
- National Institutes of Health [P01 HL028481, P01 HL090553]
- NIH NCRR [S10RR026744]
- National Science Foundation [EPS 0236913, MCB 0455318, 0920663, DBI 0521587]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0920663] Funding Source: National Science Foundation
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.
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