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

被引：140

作者：

Pello, Rosa ^{[1
,2
]}

Martin, Miguel A. ^{[1
,2
]}

Carelli, Valerio ^{[3
]}

Nijtmans, Leo G. ^{[4
]}

Achilli, Alessandro ^{[5
,6
]}

Pala, Maria ^{[5
]}

Torroni, Antonio ^{[5
]}

Gomez-Duran, Aurora ^{[7
,8
]}

Ruiz-Pesini, Eduardo ^{[7
,8
]}

Martinuzzi, Andrea ^{[9
]}

Smeitink, Jan A. ^{[4
]}

Arenas, Joaquin ^{[1
,2
]}

Ugalde, Cristina ^{[1
,2
]}

机构：

[1] Hosp Univ 12 Octubre, Ctr Invest, Madrid 28041, Spain

[2] CIBERER, U723, Madrid 28041, Spain

[3] Univ Bologna, Dipartimento Sci Neurol, I-40123 Bologna, Italy

[4] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mitochondrial Disorders, NL-6500 HB Nijmegen, Netherlands

[5] Univ Pavia, Dipartimento Genet & Microbiol, I-27100 Pavia, Italy

[6] Univ Perugia, Dipartimento Biol Cellulare & Ambientale, I-06123 Perugia, Italy

[7] Univ Zaragoza, CIBERER, U727, E-50013 Zaragoza, Spain

[8] Univ Zaragoza, Dept Bioquim Biol Mol & Celular, E-50013 Zaragoza, Spain

[9] Conegliano Res Ctr, E Medea Sci Inst, I-21015 Conegliano, Italy

来源：

HUMAN MOLECULAR GENETICS | 2008年 / 17卷 / 24期

关键词：

D O I：

10.1093/hmg/ddn303

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4001 / 4011

页数：11

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