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GNPS - 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 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Mioara Larion

PROVIDER: MSV000085841 | GNPS | Tue Jul 28 09:50:00 BST 2020

REPOSITORIES: GNPS

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IDH1 Mutations Induce Organelle Defects Via Dysregulated Phospholipids

Project 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.

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Project description:Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH 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 biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications. Linked studies;<a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ<a href='https://www.ebi.ac.uk/metabolights/MTBLS1973' rel='noopener noreferrer' target='_blank'>MTBLS1973</a> LCMS(CSHNeg)

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