title: Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly.
abstract: Respiratory chain (RC) complexes are organized into supercomplexes forming 'respirasomes'. The mechanism underlying the interdependence of individual complexes is still unclear. Here, we show in human patient cells that the presence of a truncated COX1 subunit leads to destabilization of complex IV (CIV) and other RC complexes. Surprisingly, the truncated COX1 protein is integrated into subcomplexes, the holocomplex and even into supercomplexes, which however are all unstable. Depletion of the m-AAA protease AFG3L2 increases stability of the truncated COX1 and other mitochondrially encoded proteins, whereas overexpression of wild-type AFG3L2 decreases their stability. Both full-length and truncated COX1 proteins physically interact with AFG3L2. Expression of a dominant negative AFG3L2 variant also promotes stabilization of CIV proteins as well as the assembled complex and rescues the severe phenotype in heteroplasmic cells. Our data indicate that the mechanism underlying pathogenesis in these patients is the rapid clearance of unstable respiratory complexes by quality control pathways, rather than their impaired assembly.
authors.affiliation: Institute for Vegetative Physiology, University of Cologne, Cologne, Germany. hue-tran.hornig@uni-koeln.de
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.forename: Takashi
authors.initials: T
authors.lastname: Tatsuta
authors.forename: Angela
authors.initials: A
authors.lastname: Buckermann
authors.forename: Maria
authors.initials: M
authors.lastname: Bust
authors.forename: Gittan
authors.initials: G
authors.lastname: Kollberg
authors.forename: Agnes
authors.initials: A
authors.lastname: Rötig
authors.forename: Martin
authors.initials: M
authors.lastname: Hellmich
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D049069:ATP-Dependent Proteases / Q000378:metabolism*; D000074183:ATPases Associated with Diverse Cellular Activities; D002478:Cells, Cultured; D018389:Codon, Nonsense; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization
chemical_list: D018389:Codon, Nonsense; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D003576:Electron Transport Complex IV; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities