Biological fractionation of lithium isotopes by cellular Na + /H + exchangers unravels fundamental transport mechanisms.

Lithium (Li) has a wide range of uses in science, medicine, and industry, but its isotopy is underexplored, except in nuclear science and in geoscience. Li and Li isotopic ratio exhibits the second largest variation on earth's surface and constitutes a widely used tool for reconstructing past oceans and climates. As large variations have been measured in mammalian organs, plants or marine species, and as Li elicits stronger effects than natural Li (∼95% Li), a central issue is the identification and quantification of biological influence of Li isotopes distribution. We show that membrane ion channels and Na-Li/H exchangers (NHEs) fractionate Li isotopes. This systematic Li enrichment is driven by membrane potential for channels, and by intracellular pH for NHEs, where it displays cooperativity, a hallmark of dimeric transport. Evidencing that transport proteins discriminate between isotopes differing by one neutron opens new avenues for transport mechanisms, Li physiology, and paleoenvironments.