Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive hematopoietic progenitor growth.

Proton export is often considered a detoxifying process in animal cells with monocarboxylate symporters co-exporting excessive lactate and protons during glycolysis or the Warburg effect. Here we report a novel mechanism by which lactate/H+ export is sufficient to induce cell growth. Increased lactate/proton export induces intracellular alkalization that 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, MCT4, or sodium-proton antiporter, NHE1 was sufficient to increase intracellular-pH (pHi) 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, carbon flux and eliminated acute myeloid leukemia-initiating-cells without cytotoxic chemotherapy. Intracellular alkalization is a primitive mechanism by which proton partitioning can directly reprogram carbon metabolism for cell growth.