title: Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways.
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.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Deceglie
authors.affiliation: Department of Reproductive Sciences, Medical Genetics, Development and Public Health, University of Trieste, Trieste, Italy.|IRCCS-Burlo Garofolo Children Hospital, Trieste, Italy.
authors.forename: P
authors.initials: P
authors.lastname: d'Adamo
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Department of Biomedical and NeuroMotor Sciences (DIBINEM), Neurology Unit, University of Bologna, Bologna, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: Valentino
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Department of Biomedical and NeuroMotor Sciences (DIBINEM), Neurology Unit, University of Bologna, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fracasso
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Roberti
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cappellari
authors.affiliation: Institute of Biomembranes and Bioenergetics (IBBE) National Research Council (CNR), Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Petrosillo
authors.affiliation: Vectis s.r.l. Cava dei Tirreni (Salerno), Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ciaravolo
authors.affiliation: Vectis s.r.l. Cava dei Tirreni (Salerno), Italy.
authors.forename: D
authors.initials: D
authors.lastname: Parente
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Giordano
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Department of Biomedical and NeuroMotor Sciences (DIBINEM), Neurology Unit, University of Bologna, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Maresca
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Department of Biomedical and NeuroMotor Sciences (DIBINEM), Neurology Unit, University of Bologna, Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Iommarini
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Del Dotto
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Ghelli
authors.affiliation: Department of Ophthalmology, and Visual Sciences, Paulista School of Medicine Federal University of Sao Paulo-UNIFESP, Sao Paulo, Brazil.
authors.forename: S R
authors.initials: SR
authors.lastname: Salomao
authors.affiliation: Department of Ophthalmology, and Visual Sciences, Paulista School of Medicine Federal University of Sao Paulo-UNIFESP, Sao Paulo, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Berezovsky
authors.affiliation: Department of Ophthalmology, and Visual Sciences, Paulista School of Medicine Federal University of Sao Paulo-UNIFESP, Sao Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Belfort
authors.affiliation: Doheny Eye Institute, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Sadun
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Department of Biomedical and NeuroMotor Sciences (DIBINEM), Neurology Unit, University of Bologna, Bologna, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Carelli
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Loguercio Polosa
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.|Institute of Biomembranes and Bioenergetics (IBBE) National Research Council (CNR), Bari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cantatore
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D029242:Optic Atrophy, Hereditary, Leber / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species