IDH1 mutations induce organelle defects via dysregulated phospholipids

Adrian Lita, Artem Pliss, Andrey Kuzmin, Tomohiro Yamasaki, Lumin Zhang, Tyrone Dowdy, Christina Burks, Natalia 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 and Mioara Larion ()
Additional contact information
Adrian Lita: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Artem Pliss: University at Buffalo, State University of New York
Andrey Kuzmin: University at Buffalo, State University of New York
Tomohiro Yamasaki: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Lumin Zhang: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Tyrone Dowdy: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Christina Burks: Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute
Natalia Val: Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute
Orieta Celiku: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Victor Ruiz-Rodado: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Elena-Raluca Nicoli: Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH)
Michael Kruhlak: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
Thorkell Andresson: Protein Characterization Laboratory of the Cancer Research Technology Program (CRTP), National Cancer Institute
Sudipto Das: Protein Characterization Laboratory of the Cancer Research Technology Program (CRTP), National Cancer Institute
Chunzhang Yang: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Rebecca Schmitt: University at Buffalo, State University of New York
Christel Herold-Mende: University Hospital Heidelberg
Mark R. Gilbert: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health
Paras N. Prasad: University at Buffalo, State University of New York
Mioara Larion: Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20752-6

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