Coordination of metal center biogenesis in human cytochrome c oxidase

Authors

Eva Nývltová, University of Miami Miller School of Medicine
Jonathan Dietz, University of Nebraska-LincolnFollow
Javier Seravalli, University of Nebraska-LincolnFollow
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Antoni Barrientos, University of Miami School of Medicine

ORCID IDs

Oleh Khalimonchuk http://orcid.org/0000-0002-3972-8678

Antoni Barrientos http://orcid.org/0000-0001-9018-3231

Document Type

Article

Date of this Version

2022

Citation

NATURE COMMUNICATIONS (2022) 13:3615

https://doi.org/10.1038/s41467-022-31413-1

Comments

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License

Abstract

Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa3- copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbors the CuB site that tightly associates with heme a3 while the COX2 subunit contains the binuclear CuA site. Here, we report that in human cells the CcO copper chaperones form macromolecular assemblies and cooperate with several twin CX9C proteins to control heme a biosynthesis and coordinate copper transfer sequentially to the CuA and CuB sites. These data on CcO illustrate a mechanism that regulates the biogenesis of macromolecular enzymatic assemblies with several catalytic metal redox centers and prevents the accumulation of cytotoxic reactive assembly intermediates.