Mutations inCOA6cause CytochromecOxidase Deficiency and Neonatal Hypertrophic Cardiomyopathy

Abstract

COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.

The subunit composition and function of mammalian cytochrome c oxidase

“…Leigh Syndrome patients with long survival (N14 years) have been described and reviewed (Aulbert et al, 2014). Recently a child with mutations in the COX assembly factor 6 (COA6) was reported, presenting with COX deficiency and neonatal hypertrophic cardiomyopathy (Baertling et al, 2015). 3.…”

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

“…Mutations in the CIV assembly factor COA5 (the human ortholog of yeast Pet191) 152 [47,52]), which carries a typical (CX 9 C) 2 motif, can give rise to a mitochondrial 153 cardiomyopathy [53]. Mutations in yet another CIV assembly factor, COA6, which contains 154 an unusual cysteine motif [20,54], destabilize the newly synthesized mitochondrial DNA-155 encoded subunit COX2 and lead to neonatal hypertrophic cardiomyopathy [54][55][56][57][58] (Tables 1 156 and 2). 157…”

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

“…The N-tail of newly synthesized COX2 is translocated across the membrane and then stabilized by interaction with COX20 (5), a transmembrane protein found to be mutated in several cases of dystonia-ataxia syndrome (6). Formation of the Cu A center has received major attention because mutations in the SCO1 and SCO2 metallochaperones specific for this function result in severe cardiomyopathies (7)(8)(9). Recently, the twin CX 9 C IMS protein COA6 has been shown to participate in COX2 maturation by interacting with SCO1, SCO2, or both (7,8,10).…”

“…Formation of the Cu A center has received major attention because mutations in the SCO1 and SCO2 metallochaperones specific for this function result in severe cardiomyopathies (7)(8)(9). Recently, the twin CX 9 C IMS protein COA6 has been shown to participate in COX2 maturation by interacting with SCO1, SCO2, or both (7,8,10). Co-immunoprecipitation (co-IP) assays have detected several COX2 stability and maturation modules containing newly synthesized COX2 and COX20-SCO1-SCO2 (5), COA6-SCO2 (11), or COA6-SCO1 (10).…”