This report describes mitochondrial complex I deficiency, nuclear type 2 (MC1DN2); MC1DN2 exhibits autosomal recessive inheritance. The human gene implicated in this disease subtype is NDUFS8, a nuclear gene that encodes a 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-23, for which a loss-of-function mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human NDUFS8 gene has not been introduced into flies.
Animals homozygous for a loss-of-function ND-23 mutation exhibit reduced lifespan, progressive neurodegeneration, abnormal mitochondrial morphology, and decreased ATP levels. Expression of wild-type ND-23 in neurons, but not in glia, substantially rescues the shortened lifespan and neurodegeneration phenotypes. Neural-specific knockdown effected by RNAi also results early death and locomotor defects; degeneration in the retina and mushroom bodies is observed. Glial-specific knockdown via RNAi confirms that survival and motor behavior of flies are not affected, but in the brain, vacuolization, lipid droplet accumulation, and degeneration are observed.
The shortened lifespan and neurodegeneration ND-23 phenotypes are enhanced by a maternally-inherited factor consistent with an mtDNA variant. This is relevant to the hypothesis that mito-nuclear interactions account for some of the phenotypic variability typical of mitochondrial diseases. Physical and genetic interactions of Dmel\ND-23 have been described; see below and in the ND-23 gene report.
[updated Apr. 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 2; MC1DN2](https://omim.org/entry/618222)
[NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 8; NDUFS8](https://omim.org/entry/602141)
NDUFS8 is a nuclear gene. [NCBI Gene, NDUFS8 (human); 2018.07.11]
Mitochondrial complex I deficiency nuclear type 2 (MC1DN2) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded NDUFS8 gene. [from MIM:618222; 2019.04.24]
NDUFS8 encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. [Gene Cards, NDUFS8; 2018.07.10]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human NDUFS8 (1 Drosophila to 1 human). Dmel\ND-23 shares 74% identity and 81% similarity with the human gene.
