NDUFS3 – Mitochondrial Complex I Deficiency

NDUFS3 encodes an essential catalytic subunit of complex I, and biallelic loss-of-function variants cause autosomal recessive Mitochondrial complex I deficiency. Exome sequencing in ten unrelated individuals with biochemical complex I deficiency identified two probands homozygous for c.595C>T (p.Arg199Trp), a recurrent missense variant absent from controls, which segregated with disease and abrogated complex I activity in patient cell lines ([PMID:22499348]). A quantitative immunofluorescent assay in 25 genetically confirmed patients showed loss of NDUFB8 signal and corroborated reduced NDUFS3 protein levels in nuclear-encoded complex I defects, supporting diagnostic utility ([PMID:29142257]).

A neuron-specific Ndufs3 knockout mouse recapitulated key features of human disease, including reduced complex I activity, altered brain energy metabolism, and motor incoordination; metformin treatment delayed neurological symptom onset without exacerbating lactic acidosis, highlighting potential therapeutic avenues ([PMID:33148885]). Together, these data support a loss-of-function mechanism under an autosomal recessive model with concordant functional and diagnostic assay evidence. No conflicting reports have been published. Key take-home: Biallelic NDUFS3 variants should be considered in the diagnostic evaluation of recessive mitochondrial complex I deficiency, and functional assays can guide both diagnosis and treatment development.

References

• Journal of medical genetics • 2012 • Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. PMID:22499348
• Scientific Reports • 2017 • Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency. PMID:29142257
• JCI Insight • 2020 • Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency. PMID:33148885

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