The polyamine pathway as a novel treatment target for mitochondrial disease

Primary mitochondrial diseases are caused by mutations in genes that perturb mitochondrial function and frequently affect the nervous system in patients. Complex I deficiency is the most common childhood mitochondrial disease and is caused by mutations in genes encoding complex I structural or assembly components. In patients, mutations in the complex I subunit NDUFS1 typically cause severe and rapidly progressive leukoencephalopathy and death during childhood. We developed a Drosophila model of complex I deficiency using knockdown of the NDUFS1 homolog ND-75 in neurons (ND-75 KD). ND-75 KD flies exhibit severely reduced locomotion, shortened lifespan and seizures, and so model the phenotypes seen in complex I deficiency patients.To identify novel mechanisms that contribute to the pathogenesis of complex I deficiency, we performed transcriptomics and untargeted metabolomics of ND-75 KD head tissue. This multiomics approach showed that the polyamine pathway was disrupted in ND-75 KD flies. Polyamines have multiple key roles in cellular physiology and have beneficial effects in models of cognitive ageing. We therefore hypothesised that disruption of polyamine metabolism contributes to nervous system pathology in complex I deficiency. To test this hypothesis, we overexpressed the polyamine pathway rate limiting enzyme ornithine decarboxylase (ODC1) in ND-75 KD fly neurons. We find that ODC1 overexpression ameliorates the seizure and climbing phenotypes in ND-75 KD flies, and this is dependent on the neuronal subtype targeted.We are currently investigating the underlying mechanisms involved, but our studies suggest that the polyamine pathway is a potential novel treatment target for complex I deficiency.