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

Poët, Mallorie; Vigier, Nathalie; Bouret, Yann; Jarretou, Gisèle; Gautier, Romain; Bendahhou, Saı̈d; Balter, Vincent; Montanes, Maryline; Thibon, Fanny; Counillon, L.

doi:10.1016/j.isci.2023.106887

Cited by 6 publications

(9 citation statements)

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“…It is of interest to contrast the large Li isotope fractionation we find in the present work with two recent reports on Li isotope fractionation by Deline et al (2023); Poet et al (2023). In their work and ours, Li + isotope fractionation by the mitochondrial membrane, using ICP-MS, and Ca 2+ release, using Ca 2+ -induced fluorescence, were assessed.…”

Section: Discussionmentioning

confidence: 62%

“…Li has two stable isotopes, 6 Li and 7 Li, with varying effects on animal behaviour (Lieberman, Alexander, and Stokes, 1979;Sechzer et al, 1986;Ettenberg et al, 2020), electrical response in neuronal tissues (Esmaeilpour et al, 2023), mitochondrial Ca 2+ buffering capacity (Deline et al, 2023), and the properties of amorphous calcium phosphate (ACP) clusters and their formation (Deline et al, 2023;Fisher, 2023). A recent study also reported that the Na + /H + exchangers in fibroblast cells fractionate Li + isotopes (Poet et al, 2023). The possibility of strong isotopic effects in neuroscience is highly unexpected.…”

Section: Discussionmentioning

confidence: 98%

“…Based on Ca 2+ fluorescence results, we conclude that NCLX does not differentiate between the two Li + isotopes, suggesting an equivalence in transport function and binding site interactions for 6 Li + or 7 Li + , or an undetectable small difference between the two isotopes, under our experimental conditions and with the methods used in this work. Having found that NCLX itself does not differentiate between the Li + isotopes, we explored whether there exists an overall differentiation between the two Li + isotopes at the level of the inner mitochondrial membrane, as it is known that Li + can penetrate different biological membranes differently ( Sherman, Munsell, and Wong, 1984 ; Hughes and Birch, 1992 ; Poet et al, 2023 ). We used the ICP-MS technique to test whether the two Li + isotopes penetrate mitochondrial membranes differently by measuring the amount of each Li + isotope inside and outside mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…The possibility of different Li + isotope effects in neuroscience contexts is both puzzling and intriguing and has led to the formulation of new theoretical hypotheses invoking various quantum properties of the Li isotopes, such as its nuclear spin, that may determine their relative specific activity (Fisher, 2015;Weingarten, Doraiswamy, and Fisher, 2016;Zadeh-Haghighi and Simon, 2021). Recent work (Poet et al, 2023) reported Li + isotope fractionation via the Na + /H + exchanger in fibroblast cells, rationalizing the phenomenon in terms of a kinetic isotope effect involving the mass difference between the two isotopes. From a broader perspective, were neurophysiological Li + isotope effects to be vindicated, it would constitute a new example of quantum effects arising in biology-i.e., within the field of quantum biology (Abbott, Davies, and Pati, 2008;Mohseni et al, 2014;Marais et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies showed that Li + isotopes have different effects on animal behaviour and activity ( Lieberman, Alexander, and Stokes, 1979 ; Sechzer et al, 1986 ; Ettenberg et al, 2020 ), on electrical response in neuronal tissues ( Esmaeilpour et al, 2023 ), on uptake by the cortex ( Sherman, Munsell, and Wong, 1984 ), on animal lethality ( Alexander et al, 1982 ), on mitochondria calcium (Ca 2+ ) buffering capacity and on the properties of amorphous calcium phosphate aggregates (ACP) in vitro ( Deline et al, 2023 ; Fisher, 2023 ). A recent study reported that the sodium (Na + )/proton (H + ) exchangers in fibroblast cells fractionate Li + isotopes ( Poet et al, 2023 ). On the other hand, other studies have found no difference in biochemical or cellular processes ( Parthasarathy and Eisenberg Jr, 1984 ; Livingstone et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Effects of lithium isotopes on sodium/lithium co-transport and calcium efflux through the sodium/calcium/lithium exchanger in mitochondria

Bukhteeva,

Rahman,

Kendall

et al. 2024

Front. Physiol.

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The effects of lithium (Li) isotopes and their impact on biological processes have recently gained increased attention due to the significance of Li as a pharmacological agent and the potential that Li isotopic effects in neuroscience contexts may constitute a new example of quantum effects in biology. Previous studies have shown that the two Li isotopes, which differ in mass and nuclear spin, have unusual different effects in vivo and in vitro and, although some molecular targets for Li isotope fractionation have been proposed, it is not known whether those result in observable downstream neurophysiological effects. In this work we studied fluxes of Li+, sodium (Na+) and calcium (Ca2+) ions in the mitochondrial sodium/calcium/lithium exchanger (NCLX), the only transporter known with recognized specificity for Li+. We studied the effect of Li+ isotopes on Ca2+ efflux from heart mitochondria in comparison to natural Li+ and Na+ using Ca2+-induced fluorescence and investigated a possible Li isotope fractionation in mitochondria using inductively coupled plasma mass spectrometry (ICP-MS). Our fluorescence data indicate that Ca2+ efflux increases with higher concentrations of either Li+ or Na+. We found that the simultaneous presence of Li+ and Na+ increases Ca2+ efflux compared to Ca2+ efflux caused by the same concentration of Li+ alone. However, no differentiation in the Ca2+ efflux between the two Li+ isotopes was observed, either for Li+ alone or in mixtures of Li+ and Na+. Our ICP-MS data demonstrate that there is selectivity between Na+ and Li+ (greater Na+ than Li+ uptake) and, most interestingly, between the Li+ isotopes (greater 6Li+ than 7Li+ uptake) by the inner mitochondrial membrane. In summary, we observed no Li+ isotope differentiation for Ca2+ efflux in mitochondria via NCLX but found a Li+ isotope fractionation during Li+ uptake by mitochondria with NCLX active or blocked. Our results suggest that the transport of Li+ via NCLX is not the main pathway for Li+ isotope fractionation and that this differentiation does not affect Ca2+ efflux in mitochondria. Therefore, explaining the puzzling effects of Li+ isotopes observed in other contexts will require further investigation to identify the molecular targets for Li+ isotope differentiation.

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Section: Discussionmentioning

confidence: 62%