MT-ND6 – Mitochondrial Disease

MT-ND6 variants have been identified in multiple unrelated patients presenting with classic features of mitochondrial disease, including neurodevelopmental delay and sensorineural hearing impairment. Two probands with early-onset hearing loss and developmental delay harbored heteroplasmic MT-ND6 m.14351T>C (p.Glu108Gly) alongside other mitochondrial gene mutations, indicating its recurrent role in syndromic presentations (PMID:27155156). In a pediatric ophthalmological cohort (n=98), an MT-ND6 variant was detected in a child with nystagmus and optic neuropathy, underscoring its contribution to ocular manifestations of mitochondrial dysfunction (PMID:26448634).

Adult-onset mitochondrial complex I deficiency cases have further expanded the variant spectrum, with a novel MT-ND6 frameshift m.14512_14513del observed at >70% heteroplasmy in muscle but absent in blood, correlating with isolated neurological symptoms (PMID:32158465). Likewise, a high‐load MT-ND6 m.14597A>G (p.Ile26Thr) mutation (>90% heteroplasmy) was shown to cause Leigh syndrome with complex I impairment (PMID:34045482).

Functional studies using transmitochondrial cybrids demonstrate that the ND6 np14459G>A (p.Ala72Val) mutation reduces complex I activity by ~60% and impairs holoenzyme assembly, confirming a direct pathogenic mechanism (PMID:8622678). The G13513A (p.Asp393Asn) mutation in an adjacent ND5 subunit also disrupts complex I assembly at low mutant loads, suggesting dominant effects on enzyme stability (PMID:14520659).

Biochemical and biophysical assays reveal that ND6 substitutions perturb ubiquinone reduction kinetics and enzyme dynamics, implicating disrupted coenzyme Q binding as a mechanism of dysfunction (PMID:17894548). Moreover, ROS‐generating ND6 mutations upregulate HIF-1α via PI3K-Akt/PKC/HDAC signaling, linking mitochondrial defects to altered cellular stress responses (PMID:19801684).

Collectively, these genetic and experimental data establish a moderate-to-strong association between MT-ND6 mutations and mitochondrial disease with maternal inheritance. Systematic inclusion of MT-ND6 sequencing in suspected mitochondrial cases enhances diagnostic yield, informs prognosis, and guides management strategies.

References

• Biochemical and biophysical research communications | 2016 | Mutational screening in patients with profound sensorineural hearing loss and neurodevelopmental delay: Description of a novel m.3861A>C mitochondrial mutation in the MT-ND1 gene PMID:27155156
• Acta ophthalmologica | 2016 | Genetic aetiology of ophthalmological manifestations in children - a focus on mitochondrial disease-related symptoms. PMID:26448634
• Frontiers in genetics | 2020 | Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency. PMID:32158465
• Scientific reports | 2021 | A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome. PMID:34045482
• Molecular and cellular biology | 1996 | Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. PMID:8622678
• Annals of neurology | 2003 | Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. PMID:14520659
• The Biochemical journal | 2008 | Leber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzyme. PMID:17894548
• The Journal of biological chemistry | 2009 | Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. PMID:19801684

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