Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.

Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes involved in central metabolism. In humans, mutations in the lipoyl transferase LIPT2 impair mitochondrial protein lipoylation and cause severe metabolic disease. Here, we investigated the Drosophila homolog, lipT2, in vivo. lipT2 mutants exhibited locomotor defects and shortened lifespan, accompanied by markedly reduced lipoylation of pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH). Loss of lipT2 impaired glucose oxidation and disrupted tricarboxylic acid (TCA) cycle activity, leading to reduced mitochondrial energy production. Metabolomic analysis revealed altered amino acid homeostasis, including a marked reduction in aspartate, a key TCA cycle-derived metabolite. These findings demonstrate that defective lipoylation disrupts central metabolic processes and energy homeostasis.