Effects of lithium on mortality and metabolite profiles in Drosophila lithium-inducible SLC6 transporter mutants

Lithium has long been the primary treatment for bipolar disorder and shows promise for managing other neurological and psychiatric conditions. We previously identified the Lithium-inducible SLC6 transporter (List) in Drosophila melanogaster as a gene significantly upregulated in response to lithium chloride supplementation. List encodes a putative amino acid transporter belonging to the Na⁺-dependent solute carrier family 6. Here, we show that List is expressed in the Malpighian tubules, glia, and hindgut. RNA interference-mediated List knockdown in the Malpighian tubules drastically increases lithium-induced mortality. Additionally, List loss-of-function mutants (List^TG4.2) accumulate six times more internal lithium than controls after lithium exposure. Metabolomic analysis revealed disrupted amino acid metabolism and a shift toward a more oxidized cellular redox state in lithium-treated List^TG4.2 mutants. Overall, our findings suggest that List protects flies from lithium toxicity by regulating internal lithium levels and maintaining metabolic and redox balance.