This report describes mitochondrial complex I deficiency, nuclear type 2 (MC1DN1); MC1DN1 exhibits autosomal recessive inheritance. The human gene implicated in this disease subtype is NDUFS4, a nuclear gene that encodes an accessory subunit of NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the mitochondrial electron transport chain. There is a single fly ortholog, Dmel\ND-18, for which RNAi-targeting constructs have been generated.
The human NDUFS8 gene has not been introduced into flies.
Ubiquitous knockdown of Dmel\ND-18, effected by RNAi, results in a high percentage of pupal lethality; surviving adults exhibit reduced lifespan, severe feeding impairment, and locomotor defects. Larvae appear to ingest less food than control animals. In adults, the oxidative phsophorylation activity of Complex I is reduced, while the activity of Complex III is increased. Muscle-specific knockdown effected by RNAi results in comparable lifespan, feeding and locomotor defects. Pan-neuronal knockdown results in much milder phenotypes. Extensive physical interactions have been described for Dmel\ND-18; see below and in the ND-18 gene report.
[updated July 2019 by FlyBase; FBrf0222196]
Mitochondrial complex I deficiency causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, and liver disease. [from MIM:252010; 2016.08.12]
[MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 1; MC1DN1](https://omim.org/entry/252010)
[NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 4; NDUFS4](https://omim.org/entry/602694)
NDUFS4 is a nuclear gene. [NCBI Gene, NDUFS4 (human); 2018.07.11]
Mitochondrial complex I deficiency nuclear type 1 (MC1DN1) is caused by homozygous mutation in the nuclear-encoded NDUFS4 gene. [from MIM:252010; 2019.04.24]
NDUFS4 encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. [Gene Cards, NDUFS4; 2018.07.11]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human NDUFS4 (1 Drosophila to 1 human). Dmel\ND-18 shares 55% identity and 76% similarity with the human gene.
