IDH1 Mutations Induce Organelle Defects via Dysregulated Phospholipids

Mioara Larion, et al.

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Mar 23, 2020

Received Date: 5th March 20

Mioara Larion, Adrian Lita, Artem Pliss, Andrey Kuzmin, Tomohiro Yamasaki, Lumin Zhang, Tyrone Dowdy, Christina Burks, Natalia de Val, Orieta Celiku, Victor Ruiz-Rodado, Elena-Raluca Nicoli, Michael Kruhlak, Thorkell Andresson, Sudipto Das, Chunzhang Yang, Rebecca Schmitt, Christel Herold-Mende, Mark R Gilbert, Paras N Prasad

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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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