IDH1 mutations induce organelle defects via dysregulated phospholipids

Abstract

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.

A mutation in transmembrane protein 135 impairs lipid metabolism in mouse eyecups

“…IDH1 is an isocitrate dehydrogenase enzyme found in the cytoplasm as well as on peroxisomes that catalyzes the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate 30 . Loss-of-function mutations in human IDH1 lead to increased monosaturated fatty acids and increased SCD expression in infiltrating gliomas 31 . Since there is increased eyecup Scd1 expression in Tmem135 FUN025 / FUN025 mice and SCD1 is the rate-limiting enzyme for the conversion of saturated fatty acids to monounsaturated fatty acids 32 , the increased Idh1 expression in Tmem135 FUN025 / FUN025 mouse eyecups may occur to decrease the amount of monounsaturated fatty acids.…”

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

“…Interestingly, it has been reported that IDH1mut induced altered lipid metabolism. Doxycycline–driven IDH1mut overexpression in U251 impaired the PUFAs contents in endoplasmic reticulum and golgi [ 30 ] and cholesterol homeostasis [ 31 ], suggesting altered intracellular lipid contents may affect the localization and expression of FABP7. Furthermore, there may be a difference in the therapeutic target is different between IDH1wt and IDH1mut glioma considering the different lipid metabolite.…”

Unveiling Cancer Metabolism through Spontaneous and Coherent Raman Spectroscopy and Stable Isotope Probing

“…Its signal also shows an intensity that is linearly proportional to the concentration of the targeted molecules and is free of nonresonant background. With the intensity of the signal proportional to the concentration of the metabolites of interest, semi-quantitative molecular profiling of single cells and tissues is possible [23][24][25][26][27]. SRS would be a complementary tool to spontaneous Raman scattering and simultaneously using the two can be beneficial (Table 1) [28].…”