SUMMARY 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 mTOR abundance in lipin-1-haploinsufficent and –deficient muscle. Lipin-1 restoration in skeletal muscle prevents myonecrosis and statin toxicity in vivo, and activated protein kinase D rescues autophagic flux and lipid homeostasis 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.

Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.

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Cerebellar granule cells from 5-12-day-old rats can be incubated in suspension at 37°C for up to 3 hr with minimal decline in viability. Methyl mercury was found to produce time-and concentrationdependent cell killing with >85% cell death after 3 hr exposure to a concentration of 20 PM. Previously characterized inhibition of protein and RNA synthesis as well as known methyl mercury-induced defects in cellular ATP production have been shown to be incapable of causing this degree of cell death. Here we report that methyl mercury induced a concentration-dependent increase in membrane lipoperoxidation and a rapid decline in reduced glutathione in this cerebellar neuronal preparation. Hydrogen peroxide at 5 mM was found to closely reproduce each of the cytotoxic effects manifested by methyl mercury suggesting that oxidizing conditions produced by methyl mercury may account for the observed cell death. Methyl mercury-induced hpoperoxidation was not the cause of cell death since malonaldehyde production could be blocked by a-tocopherol or EDTA without appreciably protecting against cell death. Significant protection from methyl mercury-induced cell death was observed, with EGTA, deferoxamine and KCN. We propose that oxidative events contribute to the toxic mechanism of action of methyl mercury in isolated cerebellar granule neurons.

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