This report describes mitochondrial complex I deficiency, NDUFS1-related. The human gene implicated in this subtype of complex I deficiency is NDUFS1, a nuclear gene that encodes the largest subunit of mitochondrial complex I. There is a single fly ortholog, Dmel\ND-75, for which RNAi-targeting constructs and an allele caused by insertional mutagenesis have been generated.
The human NDUFS1 gene has not been introduced into flies.
Using cell-type specific RNAi knockdown, it was found that reduction of Dmel\ND-75 in both neurons and glia contribute to the disease phenotype; clinical features of the disease are recapitulated, including neuronal loss, mitochondrial enlargement, motor dysfunction and early death.
Muscle-specific knockdown of ND-75 does not affect overall muscle integrity, although it results in larvae with smaller muscles; mitochondria embedded in the myofibers are disrupted and morphologically abnormal. Unexpectedly, it was found that complex I disruption in the larval muscle remotely impairs mitochondrial activity in the fat body; lipid accumulation in the fat body results (an obesity phenotype). This nonautonomous phenomenon is described as mitochondrial synchrony: synchronized regulation of mitochondrial activity in distinct organs or tissues.
Multiple physical and genetic interactions of Dmel\ND-75 have been described; see below and in the ND-75 gene report.
[updated Jul. 2018 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 5; MC1DN5](https://omim.org/entry/618226)
[NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 1; NDUFS1](https://omim.org/entry/157655)
This form of mitochondrial complex I deficiency is caused by homozygous or compound heterozygous mutation in the nuclear-encoded NDUFS1 gene. [from MIM:157655; 2016.08.24]
The NDUFS1 protein locates at the mitochondrial inner membrane. It has NADH dehydrogenase activity and oxidoreductase activity, and transfers electrons from NADH to the mitochondrial respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized.
NDUFS1 ( NADH:ubiquinone oxidoreductase core subunit S1) is an integral part of the mitochondrial respiratory chain and is one of several Fe-S (iron-sulfur) proteins operating within complex I of the mitochondrial respiratory chain assembly (Ragan, 1987). Functionally, this enzyme is thought to be the first of the Fe-S proteins to accept electrons from an NADH-flavoprotein reductase within the complex. [from MIM:157655; 2016.08.23]
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human NDUFS1 (1 Drosophila to 1 human; reciprocal best hit). Dmel\ND-75 shares 61% identity and 75% similarity with the human gene.
