Pivotal Role of Exogenous Pyruvate in Human Natural Killer Cell Metabolism

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2025 Jan 3

PMID 39753710

Authors

Nicolas Kern Coquillat

Louis Picq

Ameline Hamond

Pierre Megy

Sarah Benezech

Annabelle Drouillard

Nina Lager-Lachaud

Edern Cahoreau

Marielle Moreau

Lucie Fallone

Anne-Laure Mathieu

Floriant Bellvert

Carine Nizard

Anne-Laure Bulteau

Thierry Walzer

Antoine Marcais

Affiliations

Soon will be listed here.

Abstract

Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate-malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings.

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