A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells

Hee Chan Yoo, Seung Joon Park, Miso Nam, Juwon Kang, Kibum Kim, Joo Hye Yeo, Joon Ki Kim, Yunkyung Heo, Hee Seung Lee, Myeong Youl Lee, Chang Woo Lee, Jong Soon Kang, Yun Hee Kim, Jinu Lee, Junjeong Choi, Geum Sook Hwang, Seungmin Bang, Jung Min Han

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondrial localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2α. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic cancer cells. SLC1A5 variant knockdown and overexpression alter cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for cancer metabolic reprogramming. Despite the importance of glutamine in cancer metabolism, the mitochondrial glutamine transporter has long been unknown. Yoo et al. show that a variant of SLC1A5 has a mitochondrial targeting signal for mitochondrial localization and is induced by HIF-2α. SLC1A5 variant knockdown suppressed cancer cell growth, supporting an oncogenic role.

Original languageEnglish
Pages (from-to)267-283.e12
JournalCell Metabolism
Volume31
Issue number2
DOIs
Publication statusPublished - 2020 Feb 4

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Yoo, H. C., Park, S. J., Nam, M., Kang, J., Kim, K., Yeo, J. H., Kim, J. K., Heo, Y., Lee, H. S., Lee, M. Y., Lee, C. W., Kang, J. S., Kim, Y. H., Lee, J., Choi, J., Hwang, G. S., Bang, S., & Han, J. M. (2020). A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metabolism, 31(2), 267-283.e12. https://doi.org/10.1016/j.cmet.2019.11.020