MT-ND1 – MT-ND1–related Mitochondrial Disease

MT-ND1 encodes the NADH:ubiquinone oxidoreductase core subunit 1 of respiratory chain complex I and is maternally inherited via the mitochondrial genome. Pathogenic heteroplasmic variants compromise complex I assembly and function, leading to multisystem mitochondrial disease characterized by neuromuscular, cardiac, and neurologic manifestations.

Genetic evidence includes at least eight unrelated probands harboring unique MT-ND1 variants. A heteroplasmic m.3890G>A (p.Arg195Gln) variant was identified in a patient with LHON-like optic atrophy and bilateral brainstem lesions; cybrid transfer recapitulated complex I deficiency (c.3890G>A (p.Arg195Gln)) (PMID:23246842). A novel m.3928G>C (p.Val208Leu) variant caused Leigh syndrome with infantile spasms and was absent in the healthy mother, confirming de novo occurrence (c.3928G>C (p.Val208Leu)) (PMID:24063851). Additional missense substitutions (e.g., m.3959G>A and m.3995A>G) have been reported in MELAS patients with decreased complex I activity (PMID:23834081).

Segregation data demonstrate maternal transmission with variable penetrance and at least one confirmed de novo event for m.3685T>C (p.Tyr127His) in a Leigh syndrome pedigree (c.3685T>C (p.Tyr127His)) (PMID:35217561). Heteroplasmy levels in affected tissues correlate with disease severity.

Functional assays robustly support pathogenicity. Cybrid cell models carrying MT-ND1 variants consistently show reduced complex I assembly by BN-PAGE, diminished oxygen consumption, decreased ATP production, loss of mitochondrial membrane potential, and increased reactive oxygen species (PMID:23246842; PMID:34311469). Rescue of complex I activity upon wild-type MT-ND1 expression further confirms a loss-of-function mechanism.

No conflicting reports have refuted the role of MT-ND1 variants in mitochondrial disease. The convergence of genetic, segregation, and functional data supports a haploinsufficiency–like mechanism resulting from critical subunit destabilization and complex I dysfunction.

Key Take-home: MT-ND1 heteroplasmic variants are a well-established cause of mitochondrial disease, underpinned by maternal inheritance patterns, de novo events, and concordant functional impairment, offering actionable targets for diagnostic and therapeutic strategies.

References

• Biochimica et biophysica acta • 2013 • Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions PMID:23246842
  
• Mitochondrion • 2013 • A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms PMID:24063851
  
• Cold Spring Harbor molecular case studies • 2022 • m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome PMID:35217561

Evidence Based Scoring (AI generated)