title: Mitochondrial Cytochrome c Oxidase Biogenesis Is Regulated by the Redox State of a Heme-Binding Translational Activator.
abstract: OBJECTIVE
  Mitochondrial cytochrome c oxidase (COX), the last enzyme of the respiratory chain, catalyzes the reduction of oxygen to water and therefore is essential for cell function and viability. COX is a multimeric complex, whose biogenesis is extensively regulated. One type of control targets cytochrome c oxidase subunit 1 (Cox1), a key COX enzymatic core subunit translated on mitochondrial ribosomes. In Saccharomyces cerevisiae, Cox1 synthesis and COX assembly are coordinated through a negative feedback regulatory loop. This coordination is mediated by Mss51, a heme-sensing COX1 mRNA-specific processing factor and translational activator that is also a Cox1 chaperone. In this study, we investigated whether Mss51 hemylation and Mss51-mediated Cox1 synthesis are both modulated by the reduction-oxidation (redox) environment.
  
  
  RESULTS
  We report that Cox1 synthesis is attenuated under oxidative stress conditions and have identified one of the underlying mechanisms. We show that in vitro and in vivo exposure to hydrogen peroxide induces the formation of a disulfide bond in Mss51 involving CPX motif heme-coordinating cysteines. Mss51 oxidation results in a heme ligand switch, thereby lowering heme-binding affinity and promoting its release. We demonstrate that in addition to affecting Mss51-dependent heme sensing, oxidative stress compromises Mss51 roles in COX1 mRNA processing and translation.
  
  
  METHODS
  H2O2-induced downregulation of mitochondrial translation has so far not been reported. We show that high H2O2 concentrations induce a global attenuation effect, but milder concentrations specifically affect COX1 mRNA processing and translation in an Mss51-dependent manner.
  
  
  CONCLUSIONS
  The redox environment modulates Mss51 functions, which are essential for regulation of COX biogenesis and aerobic energy production.
authors.affiliation: 1 Department of Neurology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Iliana C
authors.initials: IC
authors.lastname: Soto
authors.affiliation: 1 Department of Neurology, University of Miami Miller School of Medicine , Miami, Florida.|2 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Antoni
authors.initials: A
authors.lastname: Barrientos
mesh_terms: D003576:Electron Transport Complex IV / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D006418:Heme; D003576:Electron Transport Complex IV