Abstract
Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that modulate LHON penetrance must take into account also the exposure to environmental triggers such as tobacco smoke.
Highlights
The mitochondrial DNA (mtDNA) mutations are necessary but not sufficient to cause Leber’s hereditary optic neuropathy (LHON),[13] with penetrance being on average about 50%
By studying different experimental systems we found that the unaffected mutation carriers had a significantly higher mtDNA copy number and mitochondrial mass compared with their affected relatives,[18] indicating that efficiently increasing mitochondrial biogenesis may overcome the pathogenic effect of the mtDNA mutation
We previously studied the large SOA-BR LHON family from Brazil and an Italian cohort of 39 LHON families demonstrating that a significant difference characterizes unaffected mutation carriers compared with affected individuals in terms of mtDNA copy number and
Summary
The mtDNA mutations are necessary but not sufficient to cause LHON,[13] with penetrance being on average about 50%. T4C and m.11778G4A mutations has been consistently documented in patients of European descent, indicating that mtDNA background modulates to a certain extent disease penetrance.[14,15] in a prototypical LHON maternal lineage, despite all the individuals carry the homoplasmic mtDNA mutation regardless the haplogroup, only some develop the disease, pointing to further factors that may be genetic and environmental.[16] male prevalence and incomplete penetrance remain the two investigated and problematic issues in LHON Both issues have been recently mechanistically related to the efficiency of compensatory mitochondrial biogenesis.[17,18] Estrogens ameliorate mitochondrial dysfunction by activating mitochondrial biogenesis, suggesting that females are naturally protected during their fertile period.[17,19] by studying different experimental systems (blood cells, skeletal muscle, skin-derived fibroblasts and ocular tissue) we found that the unaffected mutation carriers had a significantly higher mtDNA copy number and mitochondrial mass compared with their affected relatives,[18] indicating that efficiently increasing mitochondrial biogenesis may overcome the pathogenic effect of the mtDNA mutation. Unaffected mutation carriers displayed the most efficient capacity for reactive oxygen species (ROS) detoxification, which was not hampered by exposure to cigarette derivatives
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