Publications by authors named "Junmei Yi"

4 Publications

  • Page 1 of 1

Mitochondrial NADP(H) generation is essential for proline biosynthesis.

Science 2021 05 22;372(6545):968-972. Epub 2021 Apr 22.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The coenzyme nicotinamide adenine dinucleotide phosphate (NADP) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but rather led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.
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http://dx.doi.org/10.1126/science.abd5491DOI Listing
May 2021

Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31189-31197. Epub 2020 Nov 23.

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;

Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
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http://dx.doi.org/10.1073/pnas.2017152117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733797PMC
December 2020

Aiming at Cancer In Vivo: Ferroptosis-Inducer Delivered by Nanoparticles.

Cell Chem Biol 2019 05;26(5):621-622

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address:

Induction of ferroptosis has emerged as a potential cancer therapeutic approach. In this issue of Cell Chemical Biology, Zhang et al. (2019) demonstrate the anticancer efficacy and safety of the ferroptosis inducer imidazole ketone erastin (IKE) in a xenograft model by using a nanoparticle-based delivery system.
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http://dx.doi.org/10.1016/j.chembiol.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936732PMC
May 2019

Role of Mitochondria in Ferroptosis.

Mol Cell 2019 01 20;73(2):354-363.e3. Epub 2018 Dec 20.

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address:

Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.
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http://dx.doi.org/10.1016/j.molcel.2018.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338496PMC
January 2019