NDUFS3

The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.[6]

This gene encodes one of the iron-sulfur protein (IP) components of complex I.[5] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.[5][7] As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2.[7][8] It initiates the assembly of complex I in the mitochondrial matrix.[6]

Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation. [9]

Mutations in the NDUFS3 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[10][11] 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, if not impossible.[12] However, the majority of cases are caused by mutations in nuclear-encoded genes.[13][14] It 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, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[15]

NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.[7]

Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3^{tm1a(EUCOMM)Wtsi}[24][25] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[26][27][28]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[22][29] Twenty five tests were carried out on mutant mice and six significant abnormalities were observed.[22] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; males had an increased lean body mass and heart weight, and a decrease in some plasma chemistry and haematology parameters.[22]

• NDUFS1