Tissue-specific cytochrome c oxidase assembly defects due to mutations in SCO2 and SURF1
- 6 December 2005
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 392 (3), 625-632
- https://doi.org/10.1042/bj20050807
Abstract
The biogenesis of eukaryotic COX (cytochrome c oxidase) requires several accessory proteins in addition to structural subunits and prosthetic groups. We have analysed the assembly state of COX and SCO2 protein levels in various tissues of six patients with mutations in SCO2 and SURF1. SCO2 is a copper-binding protein presumably involved in formation of the Cu(A) centre of the COX2 subunit. The function of SURF1 is unknown. Immunoblot analysis of native gels demonstrated that COX holoenzyme is reduced to 10-20% in skeletal muscle and brain of SCO2 and SURF1 patients and to 10-30% in heart of SCO2 patients, whereas liver of SCO2 patients' contained normal holoenzyme levels. The steady-state levels of mutant SCO2 protein ranged from 0 to 20% in different SCO2 patient tissues. In addition, eight distinct COX subcomplexes and unassembled subunits were found, some of them identical with known assembly intermediates of the human enzyme. Heart, brain and skeletal muscle of SCO2 patients contained accumulated levels of the COX1.COX4.COX5A subcomplex, three COX1-containing subcomplexes, a COX4.COX5A subcomplex and two subcomplexes composed of only COX4 or COX5A. The accumulation of COX1.COX4.COX5A subcomplex, along with the virtual absence of free COX2, suggests that the lack of the Cu(A) centre may result in decreased stability of COX2. The appearance of COX4.COX5A subcomplex indicates that association of these nucleus-encoded subunits probably precedes their addition to COX1 during the assembly process. Finally, the consequences of SCO2 and SURF1 mutations suggest the existence of tissue-specific functional differences of these proteins that may serve different tissue-specific requirements for the regulation of COX biogenesis.Keywords
This publication has 42 references indexed in Scilit:
- Functional alteration of cytochrome c oxidase by SURF1 mutations in Leigh syndromeBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2003
- Assembly of cytochrome c oxidase: what can we learn from patients with cytochrome c oxidase deficiency?Biochemical Society Transactions, 2001
- Cytochrome c Oxidase and the Regulation of Oxidative PhosphorylationChemBioChem, 2001
- Cytochrome c Oxidase-deficient Patients Have Distinct Subunit Assembly ProfilesPublished by Elsevier BV ,2001
- Mutations of the SCO1 Gene in Mitochondrial Cytochrome c Oxidase Deficiency with Neonatal-Onset Hepatic Failure and EncephalopathyAmerican Journal of Human Genetics, 2000
- A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c OxidasePublished by Elsevier BV ,2000
- SURFEIT-1 Gene Analysis and Two-Dimensional Blue Native Gel Electrophoresis in Cytochrome c Oxidase DeficiencyBiochemical and Biophysical Research Communications, 1999
- Subunit specific monoclonal antibodies show different steady-state levels of various cytochrome-c oxidase subunits in chronic progressive external ophthalmoplegiaBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1996
- Tissue- and species-specific expression of cytochrome c oxidase isozymes in vertebratesBiochimica et Biophysica Acta (BBA) - Bioenergetics, 1990
- Biosynthesis of cytochrome c oxidase in isolated rat hepatocytesFEBS Letters, 1980