KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth.

Susanna Raho, Loredana Capobianco, Rocco Malivindi, Angelo Vozza, Carmela Piazzolla, Francesco De Leonardis, Ruggiero Gorgoglione, Pasquale Scarcia, Francesca Pezzuto, Gennaro Agrimi, Simona N. Barile, Isabella Pisano, Stephan J. Reshkin, Maria R. Greco, Rosa A. Cardone, Vittoria Rago, Yuan Li, Carlo M.T. Marobbio, Wolfgang Sommergruber, Christopher L. RileyFrancesco M. Lasorsa, Edward Mills, Maria C. Vegliante, Giuseppe E. De Benedetto, Deborah Fratantonio, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte

Research output: Contribution to journalArticlepeer-review


The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour.

Original languageEnglish
Pages (from-to)1373-1381
Number of pages9
JournalNature Metabolism
Issue number12
Publication statusPublished - Dec 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)


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