2. Academic Validation
  3. Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth

Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth

  • Blood. 2022 Jan 27;139(4):502-522. doi: 10.1182/blood.2021011563.
Cheuk Him Man 1 2 3 4,  Francois E Mercier 1 2 3 4,  Nian Liu 5,  Wentao Dong 5,  Gregory Stephanopoulos 5,  Li Jiang 6,  Yookyung Jung 7,  Charles P Lin 7,  Anskar Y H Leung 8,  David T Scadden 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA.
  • 2 Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA.
  • 3 Harvard Stem Cell Institute, Cambridge, MA.
  • 4 Ludwig Center, Harvard Medical School, Boston, MA.
  • 5 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA.
  • 6 Department of Biomedical Informatics, Harvard Medical School, Boston, MA.
  • 7 Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and.
  • 8 Division of Haematology, Department of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong SAR.
PMID: 34610101 DOI: 10.1182/blood.2021011563
Abstract

Proton export is often considered a detoxifying process in animal cells, with monocarboxylate symporters coexporting excessive lactate and protons during glycolysis or the Warburg effect. We report a novel mechanism by which lactate/H+ export is sufficient to induce cell growth. Increased intracellular pH selectively activates catalysis by key metabolic gatekeeper Enzymes HK1/PKM2/G6PDH, thereby enhancing glycolytic and pentose phosphate pathway carbon flux. The result is increased nucleotide levels, NADPH/NADP+ ratio, and cell proliferation. Simply increasing the lactate/proton symporter Monocarboxylate Transporter 4 (MCT4) or the sodium-proton antiporter NHE1 was sufficient to increase intracellular pH and give normal hematopoietic cells a significant competitive growth advantage in vivo. This process does not require additional cytokine triggers and is exploited in malignancy, where leukemogenic mutations epigenetically increase MCT4. Inhibiting MCT4 decreased intracellular pH and carbon flux and eliminated acute myeloid leukemia-initiating cells in mice without cytotoxic chemotherapy. Intracellular alkalization is a primitive mechanism by which proton partitioning can directly reprogram carbon metabolism for cell growth.

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