title: Adaptation of respiratory chain biogenesis to cytochrome c oxidase deficiency caused by SURF1 gene mutations.
abstract: The loss of Surf1 protein leads to a severe COX deficiency manifested as a fatal neurodegenerative disorder, the Leigh syndrome (LS(COX)). Surf1 appears to be involved in the early step of COX assembly but its function remains unknown. The aim of the study was to find out how SURF1 gene mutations influence expression of OXPHOS and other pro-mitochondrial genes and to further characterize the altered COX assembly. Analysis of fibroblast cell lines from 9 patients with SURF1 mutations revealed a 70% decrease of the COX complex content to be associated with 32-54% upregulation of respiratory chain complexes I, III and V and accumulation of Cox5a subunit. Whole genome expression profiling showed a general decrease of transcriptional activity in LS(COX) cells and indicated that the adaptive changes in OXPHOS complexes are due to a posttranscriptional compensatory mechanism. Electrophoretic and WB analysis showed that in mitochondria of LS(COX) cells compared to controls, the assembled COX is present entirely in a supercomplex form, as I-III₂-IV supercomplex but not as larger supercomplexes. The lack of COX also caused an accumulation of I-III₂ supercomplex. The accumulated Cox5a was mainly present as a free subunit. We have found out that the major COX assembly subcomplexes accumulated due to SURF1 mutations range in size between approximately 85-140kDa. In addition to the originally proposed S2 intermediate they might also represent Cox1-containing complexes lacking other COX subunits. Unlike the assembled COX, subcomplexes are unable to associate with complexes I and III.
authors.affiliation: Institute of Physiology, Academy of Science of the Czech Republic, v.v.i., Prague, Czech Republic.
authors.forename: Nikola
authors.initials: N
authors.lastname: Kovářová
authors.forename: Alena
authors.initials: A
authors.lastname: Cížková Vrbacká
authors.forename: Petr
authors.initials: P
authors.lastname: Pecina
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
authors.forename: Josef
authors.initials: J
authors.lastname: Houštěk
mesh_terms: D002457:Cell Extracts; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010085:Oxidative Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; C092928:Surf-1 protein; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C480024:COX5B protein, human; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III