Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency

Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency. Author summaryMutations in the mitochondrial NADH dehydrogenase cause complex I deficiency, a mitochondrial disease characterised by severe neurological problems and death in the first years of life. To understand the underlying mechanisms, we modelled complex I deficiency in the fruit fly Drosophila. Flies with complex I deficiency in neurons have problems with movement, seizures and severely reduced lifespan. Complex I deficiency in Drosophila neurons causes altered mitochondrial morphology and reduced contacts between the mitochondria and endoplasmic reticulum but does not affect ATP levels. Moreover, a stress signalling pathway called the unfolded protein response (UPR) is activated in complex I deficient neurons. Complex I deficiency also alters metabolism in the brain. Remarkably, restoring the NADH dehydrogenase activity but not the proton pumping ability of complex I in neurons, by expressing the yeast NDI1 enzyme, restores mitochondrial morphology, prevents UPR activation and rescues the behavioural and lifespan phenotypes in complex I deficient flies. Our data suggest that metabolic disruption due to loss of neuronal NADH dehydrogenase activity drive pathogenesis in complex I deficiency.

Automated summary

Mutations in subunits of the mitochondrial NADH dehydrogenase cause severe neurological diseases and death in infancy. The underlying mechanisms and effective treatments for complex I deficiency remain poorly understood. By studying Drosophila with complex I deficiency, it was found that neuronal deficiency leads to locomotor defects, seizures, reduced lifespan, mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts, and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons.