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Human Molecular Genetics Advance Access originally published online on September 19, 2008
Human Molecular Genetics 2008 17(24):4001-4011; doi:10.1093/hmg/ddn303
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease

Rosa Pello1,2, Miguel A. Martín1,2, Valerio Carelli3, Leo G. Nijtmans4, Alessandro Achilli5,6, Maria Pala5, Antonio Torroni5, Aurora Gómez-Durán7,8, Eduardo Ruiz-Pesini7,8, Andrea Martinuzzi9, Jan A. Smeitink4, Joaquín Arenas1,2 and Cristina Ugalde1,2,*

1 CIBERER-U723 2 Centro de Investigación, Hospital Universitario 12 de Octubre, Madrid 28041, Spain, 3 Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna 40123, Italy, 4 Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands, 5 Dipartimento di Genetica e Microbiologia, Università di Pavia, Pavia 27100, Italy, 6 Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia 06123, Italy, 7 CIBERER-U727 8 Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza 50013, Spain 9 E. Medea Scientific Institute, Conegliano Research Centre, Conegliano 21015, Italy

* To whom correspondence should be addressed at: Centro de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, Madrid 28041, Spain. Tel: +34 913908763; Fax: +34 913908544; Email: cugalde{at}h12o.es

Received August 7, 2008; Accepted September 16, 2008

Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disorder, is mostly due to three mitochondrial DNA (mtDNA) mutations in respiratory chain complex I subunit genes: 3460/ND1, 11778/ND4 and 14484/ND6. Despite considerable clinical evidences, a genetic modifying role of the mtDNA haplogroup background in the clinical expression of LHON remains experimentally unproven. We investigated the effect of mtDNA haplogroups on the assembly of oxidative phosphorylation (OXPHOS) complexes in transmitochondrial hybrids (cybrids) harboring the three common LHON mutations. The steady-state levels of respiratory chain complexes appeared normal in mutant cybrids. However, an accumulation of low molecular weight subcomplexes suggested a complex I assembly/stability defect, which was further demonstrated by reversibly inhibiting mitochondrial protein translation with doxycycline. Our results showed differentially delayed assembly rates of respiratory chain complexes I, III and IV amongst mutants belonging to different mtDNA haplogroups, revealing that specific mtDNA polymorphisms may modify the pathogenic potential of LHON mutations by affecting the overall assembly kinetics of OXPHOS complexes.

New Genbank accession numbers: EU915472, EU915473, EU915474, EU915475, EU915476, EU915477, EU915478, EU915479, FJ178379, FJ178380


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