MT-ND2 – Mitochondrial Disease

MT-ND2 encodes a subunit of mitochondrial Complex I critical for oxidative phosphorylation. Pathogenic variants in MT-ND2 have been identified in isolated cases of mitochondrial myopathy. A heteroplasmic m.4831G>A (p.Gly121Asp) variant in MT-ND2 was found at 95% load in skeletal muscle of a 21-year-old man with exercise intolerance, ragged red fibers, and severe isolated Complex I deficiency (PMID:28070494). Functional studies in transmitochondrial cybrids demonstrated that a heteroplasmic m.4936C>T (p.Thr156Ile) variant impairs cell growth by 50%, reduces oxygen consumption by 60%, and alters reactive oxygen species production (PMID:22925728). E. coli models of human MT-ND2 clinical mutations recapitulate compromised Complex I assembly and activity, concordant with pathogenicity (PMID:35306226).

Genetic evidence is limited to single proband reports with minimal familial segregation; experimental concordance across multiple cellular and prokaryotic models supports a loss-of-function mechanism in Complex I deficiency. No conflicting or refuting reports have been described. Key take-home: MT-ND2 pathogenic variants cause mitochondrial disease through impaired Complex I function, warranting inclusion in diagnostic gene panels for mitochondrial myopathies.

References

• Molecular genetics and metabolism reports • 2017 • Pure myopathy with enlarged mitochondria associated to a new mutation in MTND2 gene. PMID:28070494
• FASEB journal • 2012 • Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions. PMID:22925728
• Mitochondrion • 2022 • Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli. PMID:35306226

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