Adaptation of respiratory chain biogenesis to cytochrome c oxidase deficiency caused by SURF1 gene mutations

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Abstract

The loss of Surf1 protein leads to a severe COX deficiency manifested as a fatal neurodegenerative disorder, the Leigh syndrome (LSCOX). 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 LSCOX 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 LSCOX 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 85–140 kDa. 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.

Highlights

SURF1 mutations are frequent cause of severe COX deficiency. ► Altered energy provision leads to increase of respiratory chain complexes I, III, and V. ► Adaptive changes in mitochondrial biogenesis are due to posttranscriptional events. ► All residual COX is incorporated into I–III2–IV1 supercomplex.

Abbreviations

OXPHOS
oxidative phosphorylation
COX
cytochrome c oxidase
LSCOX
Leigh syndrome on the basis of cytochrome c oxidase deficiency
cI, cII, cIII, cIV
respiratory chain complexes I–IV
cV
mitochondrial ATP synthase

Keywords

Mitochondrial disorder
SURF1 gene
Leigh syndrome
Gene expression
Oxidative phosphorylation
Cytochrome c oxidase

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