NDUFS8 – Mitochondrial Complex I Deficiency

NDUFS8 encodes the TYKY subunit of mitochondrial complex I, an essential component of the NADH:ubiquinone oxidoreductase holoenzyme. Recessive pathogenic variants in NDUFS8 disrupt complex I assembly, leading to impaired oxidative phosphorylation and multisystem presentations. Mitochondrial complex I deficiency (MONDO:0100133) manifests most commonly with infantile hypotonia (HP:0001252) and ataxia (HP:0001251), reflecting central nervous system vulnerability.

Initial candidate‐gene screening in 13 children with defined complex I deficiency identified a heterozygous NDUFS8 c.52C>T (p.Arg18Cys) variant in one patient and her unaffected mother, arguing against sole pathogenicity (PMID:16142472). Subsequent targeted sequencing in a cohort of Leigh‐like patients revealed a homozygous NDUFS8 c.236C>T (p.Pro79Leu) variant in a second child, consistent with autosomal recessive inheritance (PMID:20819849).

Exome sequencing of ten unrelated individuals with biochemically confirmed complex I deficiency uncovered rare biallelic NDUFS8 variants in two additional patients—c.476C>A (p.Ala159Asp) and c.187G>C (p.Glu63Gln)—with complementation assays demonstrating restoration of complex I activity upon wild-type cDNA expression (PMID:22499348). Overall, three unrelated probands harbored biallelic NDUFS8 missense variants, supporting a recessive disease mechanism (3 probands [PMID:20819849]; [PMID:22499348]).

Functional studies in Drosophila demonstrated that knockdown of the fly NDUFS8 orthologue (ND23) in neurons led to reduced lifespan, locomotor deficits, and decreased brain ATP, whereas glial knockdown induced lipid droplet accumulation and neurodegeneration—recapitulating human neuropathology (PMID:29285794). A recent systematic analysis of the assembly factor NDUFAF6 revealed that NDUFS8 incorporation into complex I is NDUFAF6‐dependent and that NDUFS8 overexpression rescues NDUFAF6 deficiency, underscoring the critical role of NDUFS8 in holoenzyme biogenesis (PMID:38720117).

No alternative studies have refuted the NDUFS8 association with complex I deficiency, and no unaffected segregation has been observed in recessive pedigrees. The weight of genetic and experimental data justifies a Strong clinical validity classification, with moderate genetic and functional evidence supporting pathogenicity through loss of complex I function.

Routine diagnostic sequencing of NDUFS8 is recommended for patients with suspected mitochondrial complex I deficiency. Key Take-home: Biallelic NDUFS8 variants cause autosomal recessive complex I deficiency presenting with hypotonia and ataxia, and functional assays reliably confirm pathogenicity.

References

• Journal of molecular medicine (Berlin, Germany) • 2005 • Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy. PMID:16142472
• Brain : a journal of neurology • 2010 • The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. PMID:20819849
• Journal of medical genetics • 2012 • Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. PMID:22499348
• Glia • 2018 • Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency. PMID:29285794
• Nature metabolism • 2024 • Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease. PMID:38720117

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