Partial reduction of the mitochondrial lipoyltransferase LipT2 promotes longevity and redox remodeling in Drosophila.

Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes, and mutations in the lipoyltransferase LIPT2 cause severe metabolic and neurological defects in humans. In Drosophila, two independent lipT2 loss-of-function alleles cause severe physiological abnormalities in homozygotes. Here, we show that heterozygotes for these same alleles exhibit significantly extended lifespan and delayed age-dependent decline in locomotor performance. Metabolic analysis revealed no major alterations in central carbon metabolites or cellular energy status, indicating that overall metabolic homeostasis is largely preserved. In contrast, LipT2 heterozygosity was associated with reduced DCF fluorescence and selective changes in redox-related metabolites, including glutathione and urate. LipT2 heterozygotes also exhibited enhanced resistance to paraquat-induced oxidative stress without induction of canonical antioxidant genes. These findings indicate that partial reduction of LipT2 activity is associated with selective remodeling of cellular redox homeostasis while preserving metabolic homeostasis, providing a physiological state associated with longevity and enhanced stress resistance. Thus, the effects of LipT2 deficiency are strongly dependent on gene dosage, with moderate reduction being associated with longevity and maintenance of physiological function rather than overt metabolic dysfunction.