These include 19 subunits of the complex (7 mtDNA genes, 12 nuclear genes), and 6 nuclear-encoded accessory factors that are required for its proper assembly, stability, or maturation ( Supplementary Table 1). To date, 25 genes underlying human CI deficiency have been identified via candidate gene sequencing, linkage analysis, or homozygosity mapping. Estimates suggest that roughly 15–20% of isolated CI deficiency cases are due to mutations in the mtDNA, while the rest are likely caused by nuclear defects 7, 8, though most of these mutations remain unknown. The diagnosis of CI deficiency is challenging given its clinical and genetic heterogeneity and usually relies on biochemical assessment of biopsy material 5, 6. CI deficiency can present in infancy or early adulthood and shows a wide range of clinical manifestations, including Leigh Syndrome, skeletal muscle myopathy, cardiomyopathy, hypotonia, stroke, ataxia, and lactic acidosis 2 – 4. Defects in CI activity are the most common type of human respiratory chain disease, which collectively has an incidence of 1 in 5000 live births 1. CI is the main entry point to the respiratory chain and catalyzes the transfer of electrons from NADH to ubiquinone while pumping protons across the mitochondrial inner membrane. Complex I (CI) of the mitochondrial respiratory chain is a large ~1MDa macromolecular machine composed of 45 protein subunits encoded by both the nuclear and mitochondrial (mtDNA) genomes.
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