Mitochondrial complex I deficiency of nuclear origin I. Structural genes

Area of Science:

• Biochemistry
• Genetics
• Mitochondrial Biology

Background:

• Complex I (NADH-ubiquinone oxidoreductase) is the largest respiratory chain complex.
• Deficiency in Complex I is the most frequent cause of mitochondrial disorders.
• It involves 38 nuclear-encoded and 7 mitochondrial-encoded subunits.

Purpose of the Study:

• To summarize recent findings on the architecture of Complex I.
• To review identified pathogenic mutations in nuclear structural Complex I genes.
• To highlight mutational hotspots and discuss genotype-phenotype correlations.

Main Methods:

• Literature review of recent data on Complex I architecture.
• Compilation and analysis of reported pathogenic mutations in nuclear genes encoding Complex I subunits.
• Identification of frequently mutated genes and assessment of genotype-phenotype relationships.

Main Results:

• The structural genes NDUFS1, NDUFS2, NDUFV1, and NDUFS4 are identified as mutational hotspots for isolated Complex I deficiency.
• Most pathogenic mutations are private (unique to individuals or families).
• Genotype-phenotype correlations are inconsistent, especially for rare recurrent mutations.

Conclusions:

• Understanding Complex I structure and mutation landscape is crucial for diagnosing and managing mitochondrial disorders.
• NDUFS1, NDUFS2, NDUFV1, and NDUFS4 are critical targets for genetic investigation in Complex I deficiency.
• The heterogeneity of mutations and inconsistent genotype-phenotype correlations pose challenges in clinical prediction.