LplA-mediated rescue of lethal myopathy and cardiomyopathy in mitochondrial lipoylation-deficient mammalian caused by Lipt1

Inherited mitochondrial metabolic disorders impair cellular energy generation and often lead to fatal metabolic crises. Mitochondrial lipoylation defects represent a severe case of such disorders that can lead to lethality but lacks effective treatment so far. In this study, we generated a viable mouse model with muscle-specific deficiency of the lipoyltransferase coded by Lipt1 to provide an in vivo preclinical model that overcomes embryonic lethality. Using this model, we examined a bacterial lipoate protein ligase A (LplA)-mediated gene therapy via adeno-associated virus (AAV) delivery. By introducing LplA alongside lipoic acid supplementation, we reconstituted a salvage pathway that bypasses the mammalian endogenous lipoylation pathway. The intervention rescued premature lethality, recovered motor function and reversed hypertrophic cardiomyopathy in the Lipt1-deficient mouse model. Mechanistically, AAV-LplA reconstitutes mitochondrial protein lipoylation and oxidative phosphorylation in situ. This energetic rescue suppresses phosphoinositide 3-kinase (PI3K)-Akt hyperactivation, thereby restoring autophagic clearance and subsequently contributing to the recovery of the pathological phenotype. This study established AAV-LplA as a promising gene-delivery strategy for rescuing lethal mitochondrial lipoylation disorders.