Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production
Background Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disru...
| Main Authors: | , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
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| _version_ | 1826308860961357824 |
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| author | Blaszczak, W Williams, H Swietach, P |
| author_facet | Blaszczak, W Williams, H Swietach, P |
| author_sort | Blaszczak, W |
| collection | OXFORD |
| description | Background
Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production.
Methods
Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype.
Results
MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes.
Conclusions
We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.
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| first_indexed | 2024-03-07T07:27:13Z |
| format | Journal article |
| id | oxford-uuid:522157f8-5bbd-4765-b6ed-6b9f739f6d4a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:27:13Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:522157f8-5bbd-4765-b6ed-6b9f739f6d4a2022-11-24T10:22:42ZAutoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid productionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:522157f8-5bbd-4765-b6ed-6b9f739f6d4aEnglishSymplectic ElementsSpringer Nature2022Blaszczak, WWilliams, HSwietach, PBackground Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production. Methods Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype. Results MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes. Conclusions We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux. |
| spellingShingle | Blaszczak, W Williams, H Swietach, P Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title | Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title_full | Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title_fullStr | Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title_full_unstemmed | Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title_short | Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production |
| title_sort | autoregulation of h lactate efflux prevents monocarboxylate transport mct inhibitors from reducing glycolytic lactic acid production |
| work_keys_str_mv | AT blaszczakw autoregulationofhlactateeffluxpreventsmonocarboxylatetransportmctinhibitorsfromreducingglycolyticlacticacidproduction AT williamsh autoregulationofhlactateeffluxpreventsmonocarboxylatetransportmctinhibitorsfromreducingglycolyticlacticacidproduction AT swietachp autoregulationofhlactateeffluxpreventsmonocarboxylatetransportmctinhibitorsfromreducingglycolyticlacticacidproduction |