Journal
HUMAN MOLECULAR GENETICS
Volume 17, Issue 24, Pages 4001-4011Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn303
Keywords
-
Funding
- Fundacion de Investigacion Biomedica del Hospital Universitario 12 de Octubre/Agencia Pedro Lain Entralgo
- Instituto de Salud Carlos III (ISCIII) [04/00011, PI05-0379, PI05-0647]
- Fundacion ARAID
- Telethon-Italy [GGP06233]
- Progetti Ricerca Interesse Nazionale 2007 ( Italian Ministry of the University)
- Fundacion de Investigacion Medica Mutua Madrilena [2005-069]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available