Granat L, Knorr DY, Ranson DC, Hamer EL, Chakrabarty RP, Mattedi F, Fort-Aznar L, Hirth F, Sweeney ST, Vagnoni A, Chandel NS, Bateman JM.
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.
Drosophila / metabolism
Electron Transport Complex I / genetics
Electron Transport Complex I / metabolism
NADH Dehydrogenase / genetics
Neurons / metabolism
Saccharomyces cerevisiae* / genetics
Saccharomyces cerevisiae* / metabolism
Saccharomyces cerevisiae Proteins* / genetics
Saccharomyces cerevisiae Proteins* / metabolism
Unfolded Protein Response / genetics