File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

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

TitleProton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth
Authors
Issue Date27-Jan-2022
PublisherAmerican Society of Hematology
Citation
Blood, 2022, v. 139, n. 4, p. 502-522 How to Cite?
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.


Persistent Identifierhttp://hdl.handle.net/10722/338946
ISSN
2023 Impact Factor: 21.0
2023 SCImago Journal Rankings: 5.272
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMan, CH-
dc.contributor.authorMercier, FE-
dc.contributor.authorLiu, NA-
dc.contributor.authorDong, WT-
dc.contributor.authorStephanopoulos, G-
dc.contributor.authorJiang, L-
dc.contributor.authorJung, Y-
dc.contributor.authorLin, CP-
dc.contributor.authorLeung, AYH-
dc.contributor.authorScadden, DT-
dc.date.accessioned2024-03-11T10:32:44Z-
dc.date.available2024-03-11T10:32:44Z-
dc.date.issued2022-01-27-
dc.identifier.citationBlood, 2022, v. 139, n. 4, p. 502-522-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/338946-
dc.description.abstract<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>-
dc.languageeng-
dc.publisherAmerican Society of Hematology-
dc.relation.ispartofBlood-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleProton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth-
dc.typeArticle-
dc.identifier.doi10.1182/blood.2021011563-
dc.identifier.scopuseid_2-s2.0-85123724410-
dc.identifier.volume139-
dc.identifier.issue4-
dc.identifier.spage502-
dc.identifier.epage522-
dc.identifier.eissn1528-0020-
dc.identifier.isiWOS:000768796700009-
dc.identifier.issnl0006-4971-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats