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

Autor: Granat, Lucy, Knorr, Debbra Y., Ranson, Daniel C., Hamer, Emma L., Chakrabarty, Ram Prosad, Mattedi, Francesca, Fort-Aznar, Laura, Hirth, Frank, Sweeney, Sean T., Vagnoni, Alessio, Chandel, Navdeep S., Bateman, Joseph M.
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Zdroj: PLoS Genetics; 7/3/2023, Vol. 19 Issue 7, p1-27, 27p
Abstrakt: 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 summary: Mutations 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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