Analysis of reported SCO2 gene mutations affecting cytochrome c oxidase activity in various diseases.

Radhika Chadha,Ritika Shah,Shalini Mani

doi:10.6026/97320630010329

Abstract

A large number of mutations have been reported in SCO2 (synthesis of cytochrome c oxidase) gene in association with COX deficiency reported in different diseases such as cardioencephalomyopathy, cardiomyopathy and Leigh syndrome. However, very few of these mutations have been functionally analyzed.SCO2 gene encodes for an essential assembly factor for the formation of cytochrome c oxidase (COX). It is a nuclear encoded protein that helps in transfer of copper ions to COX. This study is an attempt to understand the possible effect of these mutations on the structure and function of SCO2 protein, by using different in silico tools. As per Human Gene Mutation Database, total 11 non synonymous variations have been reported in SCO2 gene. Among these 11 variations, only E140K and R171W are functionally proven to cause COX deficiency. They have been used as controls in this study. The remaining variations were further analyzed using ClustalW, SIFT, PolyPhen-2, GOR4, MuPro and Panther softwares. As compared to the results of the controls, most of these variations were predicted to affect the structure of SCO2 protein and hence, may cause COX dysfunction. Thus, we hypothesize that these variations have the potential to result in a disease phenotype and should be investigated by subsequent functional analyses. This will help in an appropriate diagnosis and management of the wide spectrum of COX deficiency diseases.

Highlights

Oxidative phosphorylation (OXPHOS) is the main function of mitochondria and takes place in its inner membrane
Cytochrome c oxidase (COX) is the Complex IV of this pathway. It catalyzes the transfer of reducing equivalents from cytochromec to molecular oxygen and utilizes the energy generated by this reaction to pump protons across the mitochondrial inner membrane
This helped us in elucidating that the nonvalidated mutations with almost similar or higher scores in comparison with validated mutations will be deleterious and should show disease phenotype

Summary

Introduction

Oxidative phosphorylation (OXPHOS) is the main function of mitochondria and takes place in its inner membrane. Cytochrome c oxidase (COX) is the Complex IV of this pathway. It catalyzes the transfer of reducing equivalents from cytochromec to molecular oxygen and utilizes the energy generated by this reaction to pump protons across the mitochondrial inner membrane. If COX is affected the catalysis of the transfer of reducing equivalents from cytochrome c to molecular oxygen, is disturbed. There is no other complex which can contribute to this activity in the respiratory pathway. The energy generated by COX is necessary to perform a transmembrane proton-pumping activity. This proton pumping helps in maintaining the proton motive force which drives the synthesis of ATP with the help of ATP synthase. Decreased production of ATP can lead to a wide spectrum of diseases in which organs with high energy requirements, such

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Conclusion