Serine catabolism regulates mitochondrial redox control during hypoxia

Jiangbin Ye, Jing Fan, Sriram Venneti, Ying Wooi Wan, Bruce R. Pawel, Ji Zhang, Lydia W.S. Finley, Chao Lu, Tullia Lindsten, Justin R. Cross, Guoliang Qing, Zhandong Liu, M. Celeste Simon, Joshua D. Rabinowitz, Craig B. Thompson

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO 2 and NH 4 + , resulting in net production of NADPH from NADP + . Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP + ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo , SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.

SIGNIFICANCE: In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth.

Original languageEnglish (US)
Pages (from-to)1406-1417
Number of pages12
JournalCancer Discovery
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2014

All Science Journal Classification (ASJC) codes

  • Oncology

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    Ye, J., Fan, J., Venneti, S., Wan, Y. W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., Qing, G., Liu, Z., Celeste Simon, M., Rabinowitz, J. D., & Thompson, C. B. (2014). Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discovery, 4(12), 1406-1417. https://doi.org/10.1158/2159-8290.CD-14-0250