IDH1 Mutations Induce Organelle Defects Via Dysregulated Phospholipids

Abstract

Cytosolic IDH1 enzyme plays a key, but currently unexplored, role in lipid biosynthesis. Using Raman imaging microscopy, we identified heterogeneous lipid profiles in cellular organelles attributed uniquely to IDH1 mutations. Via organelle lipidomics, we found an increase in saturated and monounsaturated fatty acids in the endoplasmic reticulum of IDH1mut cells compared with IDHWT glioma. We showed that these fatty acids incorporate into phospholipids and induce organelle dysfunctions, with prominent dilation of Golgi apparatus, which can be restored by transient knockdown of stearyl-CoA desaturase or inhibition of D-2-hydroxyglutarate (D-2HG) formation. We validated these findings using tissue from patients with glioma. Oleic acid addition led to increased sensitivity to apoptosis of IDH1mut cells compared with IDHWT. Addition of D-2HG to U251WT cells lead in increased ER and Golgi apparatus dilation. Collectively, these studies provide clinically relevant insights into the functional link between IDH1mut-induced lipid alterations and organelle dysfunction, with therapeutic implications. SignificanceGliomas are devastating tumors, with the most aggressive form--glioblastoma multiforme-- correlated with a mean patient survival of 14.5 months. No curative treatment exists to date. Low-grade glioma (LGG) with the isocitrate dehydrogenase 1 (IDH1) mutation, R132H, provides a survival benefit to patients. Understanding the unique metabolic profile of IDH1mut could provide clues regarding its association with longer survival and information about therapeutic targets. Herein, we identified lipid imbalances in organelles, generated by IDHmut in cells and patient tissue, that were responsible for Golgi dilation and that correlated with increased survival. Addition of oleic acid, which tilted the balance towards elevated levels of monounsaturated fatty acids produced IDH1mut-specific cellular apoptosis. HighlightsO_LISingle-organelle omics revealed unique alterations in lipid metabolism due to IDH1-mutations. C_LIO_LIIDH mutation leads to organelle-wide structural defects. C_LIO_LIIDH1 mutation leads to increased monounsaturated fatty acids levels in glioma cells and oligodendroglioma patient samples. C_LIO_LILipid alterations affect the membrane integrity of the Golgi apparatus. C_LIO_LIIncreased D-2HG induced SCD expression and elevated monounsaturated fatty acids C_LIO_LITilting the balance toward more-abundant monounsaturated fatty acids leads to specific IDH1mut glioma apoptosis. C_LI