MT-ATP6 – Mitochondrial Disease

MT-ATP6 encodes subunit a of the mitochondrial F₁F₀‐ATP synthase critical for oxidative phosphorylation. Heteroplasmic and homoplasmic variants in MT-ATP6 are well established as causes of multisystem mitochondrial disease, including neuropathy, ataxia, retinitis pigmentosa (NARP), and Leigh syndrome, underscoring its diagnostic importance in patients with suspected mitochondrial dysfunction.

The inheritance is strictly maternal (mitochondrial), with multiple pedigrees demonstrating transmission of MT-ATP6 point mutations across four or more generations. Over 200 unrelated probands harboring heteroplasmic variants such as m.8993T>C and m.9185T>C have been reported, with clear genotype–phenotype correlations and heteroplasmy thresholds influencing disease severity [PMID:7603783]. Segregation analysis in large cohorts confirms maternal co‐segregation in at least 19 affected relatives across families.

Variants in MT-ATP6 are predominantly missense changes affecting conserved residues within the Fo domain; the most frequent are m.8993T>G (p.Leu156Arg) and m.8993T>C (p.Leu156Pro). These variants show dose‐dependent clinical effects, from isolated ataxia or Charcot‐Marie‐Tooth disease to severe infantile Leigh syndrome, correlating with heteroplasmy levels.

Clinical series including 442 probands with CMT type 2 and distal hereditary motor neuropathy detected m.9185T>C in 1.1% of cases, revealing a novel phenotypic spectrum and reinforcing the differential in neuropathies [PMID:22933740]. Infantile and adult‐onset presentations encompass hypotonia, developmental delay, optic atrophy, seizures, episodic weakness, and cardiomyopathy.

Functional studies in patient fibroblasts, transmitochondrial cybrids, and yeast models uniformly demonstrate assembly defects of ATP synthase, diminished ATP synthesis, and altered mitochondrial membrane potential. A 2 bp deletion (9205∆TA) abolishes subunit a synthesis and destabilizes both complex V and cytochrome c oxidase, while homoplasmic T8993G/C inhibits coupled ATP synthesis by ~60% without preventing holoenzyme assembly [PMID:15265003, PMID:17121862].

The pathogenic mechanism is loss of efficient proton‐coupled ATP production with a heteroplasmy threshold effect: symptoms arise above ~60–90% mutant load. Secondary impacts include disrupted cristae morphology and impaired bioenergetic flexibility, contributing to the wide clinical heterogeneity.

Given the definitive association between MT-ATP6 variants and mitochondrial disease, comprehensive mtDNA sequencing with heteroplasmy quantification is essential in patients with multi‐organ involvement and maternal inheritance. Early identification enables genetic counseling, heteroplasmy‐guided prognosis, and tailored management.

Key take-home: MT-ATP6 variant screening is critical for diagnosing maternally inherited mitochondrial disorders and predicting clinical severity based on heteroplasmy levels.

References

• Pediatric research • 1995 • Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome. PMID:7603783
• Neurology • 2012 • Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. PMID:22933740
• The Biochemical journal • 2004 • Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206. PMID:15265003
• The Journal of biological chemistry • 2007 • ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization. PMID:17121862

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