COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase

Abstract

Highlights d COA6 is a coiled-coil-helix-coiled-coil-helix domain containing protein d COA6 preferentially interacts with SCO1 over SCO2 d COA6 acts as a disulfide reductase of SCO1 and COX2 d COA6 function can be bypassed under hypoxic conditions

What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

“…In addition, atomic absorption spectroscopy revealed that overexpressed forms of Coa6, Sco1, and Sco2 purified from E. coli were bound to Cu and at similar stoichiometries [ 46 ]. While this observation was supported by other studies [ 25 , 46 , 47 ], it was recently concluded that Coa6 does not bind copper in yeast under physiological conditions since mitochondria from both wild-type and the Coa6 KO yeast cells contained similar copper contents [ 52 ]. However, why these data did not reflect a loss of total copper due to the absence of COX biogenesis in these mitochondria was not addressed.…”

“…The missense W59C and nonsense E87* mutations were mimicked in yeast, which established that the variants could not rescue the respiratory growth defect of yeast Coa6 KO cells [ 50 ]. However, transient overexpression of the pathogenic mutation W59C COA6 could partially restore COX assembly in human COA6 KO cells [ 25 , 52 ]. In a separate study, a patient with W66R mutation in COA6 was identified with neonatal hypertrophic cardiomyopathy, muscular hypotonia, and lactic acidosis and a clear COX defect in fibroblasts [ 53 ].…”

“…In a separate study, a patient with W66R mutation in COA6 was identified with neonatal hypertrophic cardiomyopathy, muscular hypotonia, and lactic acidosis and a clear COX defect in fibroblasts [ 53 ]. Overexpression of the W66R variant in patient fibroblasts did not rescue COX activity [ 52 ].…”

“…However, the identities of the interactors are controversial, reflecting the general uncertainty regarding the precise order of interactions and events that facilitate the biogenesis of the COX Cu A site. Various reports have proposed that that COA6 specifically interacts with SCO1 [ 25 ], or SCO2 [ 46 ], or both SCO1 and SCO2 [ 47 ] and a recent study asserted that in the presence of both proteins, COA6 preferentially interacts with SCO1 over SCO2 [ 52 ]. Besides the SCO proteins, COA6 has also been shown to associate with other COX assembly factors such as COX16, which is required for COX2 biogenesis and maturation [ 27 ] and COX18 and COX20 [ 54 ].…”

“…Previously, the redox potentials of COX17, SCO1, COX2, and SCO2 have been determined as −198 mV, −277 mV, −290 mV, and less than −300 mV, respectively [ 42 , 44 , 45 , 57 ]. The redox potential of COA6 has been reported in two separate, studies as −349 ± 1 mV [ 56 ] and −330 mV [ 52 ], which is lower than the other proteins (COX17, SCO1, COX2, and SCO2) involved in copper transfer to COX. In agreement with these values, COA6 has been shown to reduce the critical disulfide bonds in COX2 and the SCO proteins [ 52 , 63 ].…”