COX20, also known as FAM36A, encodes a mitochondrial complex IV assembly factor crucial for COX2 activation. It plays a key role in the assembly of cytochrome c oxidase, the core of which consists of three mitochondrial-encoded proteins including COX2. COX20 engages with newly synthesized COX2 in the inner mitochondrial membrane, recruiting metallochaperones for copper delivery to the CuA-Site of COX2 [4,8]. It is also involved in processes like tolerance to oxidative stress and programmed cell death in Saccharomyces cerevisiae [5].

Mutations in the COX20 gene are associated with various autosomal recessive mitochondrial disorders. Patients with COX20-associated disorders often present with symptoms such as ataxia, dysarthria, dystonia, sensory neuropathy, muscle hypotonia, and visual impairment [1,2,3,6,7]. Different compound heterozygous or homozygous mutations in COX20 have been identified in affected individuals. For example, some mutations lead to a reduction of the COX20 protein, impairing the assembly and activity of mitochondrial complex IV, and ultimately causing mitochondrial bioenergetic dysfunction [7].

In conclusion, COX20 is essential for the proper assembly and function of mitochondrial complex IV. Studies on individuals with COX20 mutations have revealed its significant role in autosomal recessive mitochondrial disorders characterized by neurological and sensory impairments. Understanding COX20 function through these patient-based models helps in further elucidating the mechanisms underlying these rare disorders and may potentially guide future therapeutic strategies.

References:

1. Chen, Liqing, Liu, Yan. 2023. Clinical and genetic characteristics of children with COX20-associated mitochondrial disorder: case report and literature review. In BMC medical genomics, 16, 86. doi:10.1186/s12920-023-01513-y. https://pubmed.ncbi.nlm.nih.gov/37095481/

2. Otero, Maria G, Tiongson, Emmanuelle, Diaz, Frank, Gahl, William, Pierson, Tyler Mark. 2018. Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy. In Annals of clinical and translational neurology, 6, 154-160. doi:10.1002/acn3.661. https://pubmed.ncbi.nlm.nih.gov/30656193/

3. Li, Peizheng, Guo, Dandan, Zhang, Xiufang, Fang, Yaofeng, Liu, Yiming. 2022. Compound Heterozygous COX20 Variants Impair the Function of Mitochondrial Complex IV to Cause a Syndrome Involving Ophthalmoplegia and Visual Failure. In Frontiers in neurology, 13, 873943. doi:10.3389/fneur.2022.873943. https://pubmed.ncbi.nlm.nih.gov/35651336/

4. Lorenzi, Isotta, Oeljeklaus, Silke, Aich, Abhishek, Dennerlein, Sven, Rehling, Peter. 2017. The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis. In Biochimica et biophysica acta. Molecular cell research, 1865, 323-333. doi:10.1016/j.bbamcr.2017.11.010. https://pubmed.ncbi.nlm.nih.gov/29154948/

5. Keerthiraju, Ethiraju, Du, Chenyu, Tucker, Gregory, Greetham, Darren. 2019. A Role for COX20 in Tolerance to Oxidative Stress and Programmed Cell Death in Saccharomyces cerevisiae. In Microorganisms, 7, . doi:10.3390/microorganisms7110575. https://pubmed.ncbi.nlm.nih.gov/31752220/

6. Xu, Hongliang, Ji, Tuo, Lian, Yajun, Yin, Yuhui, Dong, Xiubing. 2019. Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy. In Human genetics, 138, 749-756. doi:10.1007/s00439-019-02026-4. https://pubmed.ncbi.nlm.nih.gov/31079202/

7. Dong, Hai-Lin, Ma, Yin, Yu, Hao, Bai, Ge, Wu, Zhi-Ying. . Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy. In Brain : a journal of neurology, 144, 2457-2470. doi:10.1093/brain/awab135. https://pubmed.ncbi.nlm.nih.gov/33751098/

8. Bourens, Myriam, Boulet, Aren, Leary, Scot C, Barrientos, Antoni. 2014. Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase. In Human molecular genetics, 23, 2901-13. doi:10.1093/hmg/ddu003. https://pubmed.ncbi.nlm.nih.gov/24403053/