MassIVE MSV000085841

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IDH1 Mutations Induce Organelle Defects Via Dysregulated Phospholipids

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Description

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 than 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 discovered increased monounsaturated fatty acids (MUFA) and their phospholipids in ER, generated by IDH1 mutation, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH1 mutation and these 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 restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced 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 a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications. [doi:10.25345/C5GJ0C] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: live-cell lipidomics ; spatial metabolomics and proteomics ; glioma ; organelle ; stearyl- 57 CoA desaturase

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Principal Investigators:
(in alphabetical order) 		Mioara Larion, National Cancer Institute, USA
Submitting User: oneillmj
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