The Study of Gene Therapy for a Cell Model of Leigh Syndrome with Mitochondrial Complex I Gene Mutation

To provide a research basis for gene therapy of Leigh syndrome caused by mitochondrial complex I gene mutation, this study explored the therapeutic effect of transducing yeast NDI1 gene on the mitochondrial ND1 gene mutation in a cell model of Leigh syndrome. It is known that m.3697G>A mutation in ND1 gene of mitochondrial complex I is one of the pathogenic mutations of Leigh syndrome. In this study, the established cybrids carrying the ND1 gene mutation were used as the cell model of Leigh syndrome with mitochondrial complex I gene mutation. The recombinant lentivirus containing the yeast NDI1 gene was transduced into the cell model. The rescued effect of expressed NDI1 protein (namely yeast complex I) on all aspects of mitochondrial complex I functions were examined. NDI1 protein was highly expressed and localized in the mitochondria after NDI1 gene being transduced into the cell model. Transduction of NDI1 gene restored complex I enzyme activity (compensation by the exogenous yeast complex I), mitochondria-related oxygen consumption level, mitochondrial coupling efficiency, and mitochondria-related ATP level, and reduced mitochondrial oxidative stress and mitophagy level. In the cell model of Leigh syndrome with mitochondrial complex I gene mutation, yeast complex I can compensate the defective oxidative phosphorylation of mitochondria, and relieve mitochondrial oxidative stress and autophagic state. The results of this study may provide a basis for the gene therapy of Leigh syndrome caused by mutations in the mitochondrial complex I genes.

CSTR: 32200.14.cjcb.2023.05.0007