35Cytosolic IDH1 enzyme plays a key, but currently unexplored, role in lipid biosynthesis. Using 36Raman imaging microscopy, we identified heterogeneous lipid profiles in cellular organelles 37 attributed uniquely to IDH1 mutations. Via organelle lipidomics, we found an increase in saturated 38 and monounsaturated fatty acids in the endoplasmic reticulum of IDH1 mut cells compared with 39 IDH WT glioma. We showed that these fatty acids incorporate into phospholipids and induce 40 organelle dysfunctions, with prominent dilation of Golgi apparatus, which can be restored by 41 transient knockdown of stearyl-CoA desaturase or inhibition of D-2-hydroxyglutarate (D-2HG) 42 formation. We validated these findings using tissue from patients with glioma. Oleic acid addition 43 led to increased sensitivity to apoptosis of IDH1 mut cells compared with IDH WT . Addition of D-2HG 44 to U251 WT cells lead in increased ER and Golgi apparatus dilation. Collectively, these studies 45 provide clinically relevant insights into the functional link between IDH1 mut -induced lipid alterations 46 and organelle dysfunction, with therapeutic implications. 48 Significance 52Gliomas are devastating tumors, with the most aggressive form-glioblastoma multiforme-53 correlated with a mean patient survival of 14.5 months. No curative treatment exists to date. Low-54 grade glioma (LGG) with the isocitrate dehydrogenase 1 (IDH1) mutation, R132H, provides a 55 survival benefit to patients. Understanding the unique metabolic profile of IDH1 mut could provide 56 clues regarding its association with longer survival and information about therapeutic targets. 57Herein, we identified lipid imbalances in organelles, generated by IDH mut in cells and patient 58 tissue, that were responsible for Golgi dilation and that correlated with increased survival. Addition 59 3 of oleic acid, which tilted the balance towards elevated levels of monounsaturated fatty acids 60 produced IDH1 mut -specific cellular apoptosis. 65 et al., 2019, Lopez et al., 2010, Victor et al., 2019). IDH1 mutations are an early event, (Lass et 66 al., 2012) are associated with a less aggressive phenotype (Parsons et al., 2008) potentially due 67 to their slow growth and need for nutrients to form D-2-hydroxyglutarate (D-2HG), and are used 68 as prognostic and diagnostic markers of glioma . In fact, the World Health Organization (WHO) 69 released a novel classification of glioma in 2016 to include IDH1 mutations as molecular markers 70 that dictate the classification (Louis et al., 2016). Much effort has been directed toward inhibiting 71 D-2HG formation(Yen et al., 2010, Han and Batchelor, 2017); however, the links between IDH1 72 mutations, tumor metabolism, and clinical manifestation are not well understood.73 Cytosolic NADP-dependent IDH1 plays an important role in lipid biosynthesis via its the 74 production of citrate and NADPH (Koh et al., 2004). The loss of the wildtype (WT) allele in gliomas 75 with the arginine 132 to histidine mutation leads to impaired citrate formation; moreov...
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