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

Abstract

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.

Mitochondrial regulation of epigenetics and its role in human diseases

“…3,23,24 Recent studies have identified an increasing number of cancers associated with various mtDNA haplogroups within the human population. Tanaka's group analyzed a population with 1,503 autopsied cases and identified genotypes for 149 polymorphisms within the coding region of the mitochondrial genome.…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Our group analyzed the effect of the most common LHON mutations that lead to complex I deficiency on the assembly of the native mitochondrial RC complexes, and also checked whether distinct mitochondrial genetic backgrounds differentially affected this process (Pello et al, 2008). This work demonstrated that the same mutation could produce different alterations not only in the assembly kinetics of complex I, but also in complexes III and IV in the mutant cells, which depended on the analyzed mitochondrial haplogroup.…”

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

“…The question of whether mtDNA haplogroups are functionally relevant has also been raised, and one recent cybrid study did find differences in mitochondrial respiratory capacity in cells containing haplogroup H versus haplogroup Uk (40). Other cybrid studies have similarly reported that common mtDNA polymorphisms may influence mitochondrial function (54,99).…”

“…It increasingly appears these polymorphisms may subtly influence mitochondrial function (40,54,99). This may apply to even extremely common synonymous mtDNA polymorphisms that do not cause amino acid substitutions (70).…”