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Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly
Author(s) -
HornigDo HueTran,
Tatsuta Takashi,
Buckermann Angela,
Bust Maria,
Kollberg Gittan,
Rötig Agnes,
Hellmich Martin,
Nijtmans Leo,
Wiesner Rudolf J
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.477
Subject(s) - biology , protein subunit , nonsense mutation , nonsense , respiratory system , genetics , mutation , nonsense mediated decay , gene , anatomy , rna , missense mutation , rna splicing
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.