Abstract

Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease.

Highlights

  • Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to three most frequent mitochondrial DNA point mutations (11778/ND4, 3460/ND1 and 14484/ND6), which affect complex I subunit genes [1]

  • Nuclear genome variation may have specific interactions with the mitochondrial DNA (mtDNA), primary cell lines derived from LHON patients, such as fibroblasts, containing both the original nuclear and mitochondrial genomes were used

  • The current study shows that mtDNA genetic variation, defined in terms of haplogroups, and environmental factors may interact becoming relevant to the pathogenesis of a human disease

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Summary

Introduction

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to three most frequent mitochondrial DNA (mtDNA) point mutations (11778/ND4, 3460/ND1 and 14484/ND6), which affect complex I subunit genes [1]. There is a solidly established evidence that a Western Eurasian mtDNA background, known as haplogroup J, plays a modifying role increasing the pathogenic potential and the penetrance of the 11778/ND4 and 14484/ND6 LHON mutations [4,5]. The functional alteration underlying this modifying effect has not been clearly elucidated, but based on accumulation of non-synonymous variants in complexes I and III, instability of supercomplexes has been originally hypothesized [4,6].

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