Abstract
Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15‐day‐old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time. rAAV9‐Ndufs3 delivered systemically into 15‐ to 18‐day‐old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9‐mediated gene replacement to revert muscle function after disease onset, we also treated post‐symptomatic, 2‐month‐old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2 months. These findings have far‐reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.
Highlights
Mitochondrial diseases have a prevalence of approximately 1:4,300 in adults (Gorman et al, 2015) and about 1:11,000 in children younger than 6 years old (Darin et al, 2001)
The conditional absence of NDUFS3 in the skeletal muscle of our CIdeficient mouse model resulted in the development of a progressive myopathy that reduced lifespan to approximately 6–8 months
We have observed an increase in the levels of several mitochondrial markers, including: SDHA, VDAC, COX1, and mitochondrial DNA (mtDNA)
Summary
Mitochondrial diseases have a prevalence of approximately 1:4,300 in adults (Gorman et al, 2015) and about 1:11,000 in children younger than 6 years old (Darin et al, 2001). Mitochondrial disorders can be caused by mutations either in mitochondrial DNA (mtDNA)- or in nuclear DNA (nDNA)encoded genes. In contrast to the maternally inherited mtDNA, nDNA defects are transmitted in a Mendelian fashion and tend to be autosomal recessive (Zeviani & Di Donato, 2004). Among many important cellular reactions, oxidative phosphorylation (OXPHOS) is a critical function of mitochondria. The OXPHOS system consists of four multi-subunit complexes (complexes I–IV) that constitute the electron transport chain (ETC) plus the FoF1-ATP synthase (complexes V) that uses the electrical and chemical gradients to drive the generation of ATP from ADP and inorganic phosphate (Pi) (Schon et al, 2012). The assembly of the OXPHOS system requires both mtDNA-encoded polypeptides and the synthesis and import of more than 100 nuclear-encoded proteins, synthesized on cytosolic ribosomes (Wiedemann & Pfanner, 2017)
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