In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2023-7-3), p. e1010793-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010793
DOI:
10.1371/journal.pgen.1010793.g001
DOI:
10.1371/journal.pgen.1010793.g002
DOI:
10.1371/journal.pgen.1010793.g003
DOI:
10.1371/journal.pgen.1010793.g004
DOI:
10.1371/journal.pgen.1010793.g005
DOI:
10.1371/journal.pgen.1010793.g006
DOI:
10.1371/journal.pgen.1010793.s001
DOI:
10.1371/journal.pgen.1010793.s002
DOI:
10.1371/journal.pgen.1010793.s003
DOI:
10.1371/journal.pgen.1010793.s004
DOI:
10.1371/journal.pgen.1010793.s005
DOI:
10.1371/journal.pgen.1010793.s006
DOI:
10.1371/journal.pgen.1010793.s007
DOI:
10.1371/journal.pgen.1010793.s008
DOI:
10.1371/journal.pgen.1010793.s009
DOI:
10.1371/journal.pgen.1010793.s010
DOI:
10.1371/journal.pgen.1010793.s011
DOI:
10.1371/journal.pgen.1010793.s012
DOI:
10.1371/journal.pgen.1010793.s013
DOI:
10.1371/journal.pgen.1010793.r001
DOI:
10.1371/journal.pgen.1010793.r002
DOI:
10.1371/journal.pgen.1010793.r003
DOI:
10.1371/journal.pgen.1010793.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2186725-2
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