This report describes mitochondrial complex I deficiency, nuclear type 3 (MC1DN3); MC1DN3 exhibits autosomal recessive inheritance. The human gene implicated in this disease subtype is NDUFS7, a nuclear gene that encodes a highly conserved subunit of the catalytic flavoprotein component of NADH:ubiquinone oxidoreductase. This enzyme complex, also known as Complex I, is the first in the mitochondrial electron transport chain. There are two orthologous genes in Drosophila, Dmel\ND-20 and Dmel\ND-20L, for which RNAi-targeting constructs have been generated.
A UAS construct of the human gene Hsap\NDUFS7 has been introduced into flies, but has not yet been investigated in any published experiments.
When ND-20 is knocked down using a ubiquitous driver in adult flies, the oxidative phosphorylation activity of Complex I is reduced, whereas the activity of Complex II, III, and IV is increased. Additionally, the percentage of flies reaching adulthood is reduced, and they have shorter lifespans. Targeted knockdown of ND-20L has been shown to lower levels of neurotransmission at larval neuromuscular junctions; the affected neurotransmission function was localized to the muscle.
[updated Jun. 2022 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 3; MC1DN3](https://omim.org/entry/618224)
[NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 7; NDUFS7](https://omim.org/entry/601825)
The clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults and Leigh syndrome is one of the most frequent clinical presentation associated with this deficiency. (Lebon et al. 2007, pubmed:17275378.)
Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult. [from MIM:252010, 2019.7.17. Three case studies of MC1DN3 with a range of symptoms can be found at MIM:618224.]
Mitochondrial complex I deficiency nuclear type 3 (MC1DN3) is caused by homozygous or compound heterozygous mutation in the NDUFS7 gene (601825) on chromosome 19p13. from MIM:618224, 2019.7.17]
The PSST subunit, encoded by the NDUFS7 gene, is one of the seven core subunits of complex I and is essential for the catalysis of electron transfer from NADH to ubiquinone. Moreover, PSST has been suggested to be involved in the very first steps of the assembly pathway of complex I, via two different potential mechanisms. (Adapted from Lebon et al. 2007, pubmed:17604671.)
One to many: 1 human gene to 2 Drosophila genes.
High-scoring ortholog of human NDUFS7 (2 Drosophila to 1 human).
High-scoring ortholog of human NDUFS7 (2 Drosophila to 1 human).
