title: Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy.
abstract: Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.
authors.affiliation: 1 Department of Radiology, Oncology and Pathology, Sapienza, University of Rome, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Luca
authors.initials: L
authors.lastname: Giordano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.forename: Annalinda
authors.initials: A
authors.lastname: Pisano
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Stefania
authors.initials: S
authors.lastname: Deceglie
authors.forename: Marina
authors.initials: M
authors.lastname: Roberti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
authors.forename: Flavio
authors.initials: F
authors.lastname: Fracasso
authors.forename: Fred N
authors.initials: FN
authors.lastname: Ross-Cisneros
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Solange R
authors.initials: SR
authors.lastname: Salomao
authors.forename: Adriana
authors.initials: A
authors.lastname: Berezovsky
authors.forename: Rubens
authors.initials: R
authors.lastname: Belfort
authors.forename: Dora Fix
authors.initials: DF
authors.lastname: Ventura
authors.forename: Milton
authors.initials: M
authors.lastname: Moraes
authors.forename: Milton
authors.initials: M
authors.lastname: Moraes Filho
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Federico
authors.initials: F
authors.lastname: Sadun
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Negri
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Sadun
authors.forename: Andrea
authors.initials: A
authors.lastname: Tancredi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mancini
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Paola
authors.initials: P
authors.lastname: Loguercio Polosa
authors.forename: Palmiro
authors.initials: P
authors.lastname: Cantatore
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063269:Mitochondrial Turnover / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: LHON penetrance; mitochondrial biogenesis; mtDNA copy number