MT-CO2 – Mitochondrial disease

MT-CO2 encodes subunit II of cytochrome c oxidase (COX, complex IV) and is essential for mitochondrial respiratory function. Pathogenic variants in MT-CO2 are maternally inherited and cause heterogeneous mitochondrial disease phenotypes, including lactic acidosis, psychosis, seizures, sensorineural hearing impairment, exercise intolerance, cataract, rod–cone dystrophy, mental deterioration, tremor, peripheral axonal neuropathy, and myopia, all reflecting complex IV deficiency in affected tissues.

Genetic evidence includes 7 unrelated probands with heteroplasmic MT-CO2 variants: m.8156delG (frameshift) (PMID:28521807), m.8163A>G (p.Tyr193Cys) (PMID:31167410), m.8091G>A (PMID:37640115), m.8088delT (frameshift) (PMID:30315213), m.7587T>C (initiation codon) segregating in a mother–son pair (PMID:10205264), m.8241T>G (p.Phe219Cys) (PMID:27422531), and one dual‐genome case with MT-CO2 and NDUFS1 variants (PMID:36918699), establishing maternal inheritance across 7 probands.

Segregation analysis in the family with m.7587T>C showed concordance of mutant load and COX-negative fibers in two affected individuals (PMID:10205264), with single-fiber studies demonstrating that >55%–65% heteroplasmy correlates with enzyme deficiency.

The variant spectrum comprises two frameshift deletions (m.8156delG, m.8088delT) and four missense or initiation codon changes (m.8163A>G, m.8091G>A, m.8241T>G, m.7587T>C), with heteroplasmy levels ranging from 26% in blood to 95% in muscle.

Functional studies demonstrate abundant COX-deficient and ragged red fibers in muscle histochemistry, assembly defects of complex IV by immunohistochemistry, decreased COX enzymatic activity, and translational impairment in yeast models of COX2 mRNA 5′ leader, with heteroplasmy correlating with biochemical deficiency in patient tissues.

No studies have refuted the MT-CO2–mitochondrial disease association. Integration of genetic and experimental data supports a Strong ClinGen classification for this gene–disease relationship, and MT-CO2 sequencing should be part of the diagnostic pipeline for suspected mitochondrial disorders with complex IV deficiency.

Key Take-home: MT-CO2 pathogenic variants cause maternally inherited mitochondrial disease characterized by complex IV deficiency, and testing of MT-CO2 is clinically indicated in patients with compatible phenotypes.

References

• BMC neurology • 2017 • Case report: a novel frameshift mutation in the mitochondrial cytochrome c oxidase II gene causing mitochondrial disorder. PMID:28521807
• Journal of clinical medicine • 2019 • A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia. PMID:31167410
• Biochimica et biophysica acta. Molecular basis of disease • 2024 • Mutation on MT-CO2 gene induces mitochondrial disease associated with neurodegeneration and intracerebral iron accumulation (NBIA). PMID:37640115
• American journal of human genetics • 1999 • An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy. PMID:10205264
• Journal of diabetes and its complications • 2017 • Whole mitochondrial genome screening of a family with maternally inherited diabetes and deafness (MIDD) associated with retinopathy: A putative haplotype associated to MIDD and a novel MT-CO2 m.8241T>G mutation. PMID:27422531
• European journal of human genetics : EJHG • 2019 • Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile. PMID:30315213
• Scientific reports • 2023 • Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis. PMID:36918699

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