RT Journal Article
SR Electronic
T1 Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.22.509020
DO 10.1101/2022.09.22.509020
A1 Lucy Granat
A1 Daniel Ranson
A1 Emma Hamer
A1 Ram Prosad Chakrabarty
A1 Francesca Mattedi
A1 Laura Fort-Aznar
A1 Frank Hirth
A1 Sean T. Sweeney
A1 Alessio Vagnoni
A1 Navdeep S. Chandel
A1 Joseph M. Bateman
YR 2022
UL http://biorxiv.org/content/early/2022/09/23/2022.09.22.509020.abstract
AB Mutations in mitochondrial complex I cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The mechanisms underlying complex I deficiency pathogenesis remain poorly understood, and as a result there are currently no available treatments. To better understand the causes of neuronal dysfunction in complex I deficiency, we modelled complex I deficiency in Drosophila by knocking down 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 leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Remarkably, we find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1 in neurons, which couples NADH oxidation to transfer of electrons into the respiratory chain, reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Metabolomic analysis shows that NDI1 expression also reconfigures neuronal metabolism and implicates increased GABA levels as a contributor to the neurological manifestations of complex I deficiency. Together, these data indicate that NDI1 abrogates UPR signalling and reprogrammes metabolism to alleviate neuronal dysfunction caused by neuronal complex I deficiency.Competing Interest StatementThe authors have declared no competing interest.