Cargando…

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Giordano, Carla, Iommarini, Luisa, Giordano, Luca, Maresca, Alessandra, Pisano, Annalinda, Valentino, Maria Lucia, Caporali, Leonardo, Liguori, Rocco, Deceglie, Stefania, Roberti, Marina, Fanelli, Francesca, Fracasso, Flavio, Ross-Cisneros, Fred N., D’Adamo, Pio, Hudson, Gavin, Pyle, Angela, Yu-Wai-Man, Patrick, Chinnery, Patrick F., Zeviani, Massimo, Salomao, Solange R., Berezovsky, Adriana, Belfort, Rubens, Ventura, Dora Fix, Moraes, Milton, Moraes Filho, Milton, Barboni, Piero, Sadun, Federico, De Negri, Annamaria, Sadun, Alfredo A., Tancredi, Andrea, Mancini, Massimiliano, d’Amati, Giulia, Loguercio Polosa, Paola, Cantatore, Palmiro, Carelli, Valerio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914475/
https://www.ncbi.nlm.nih.gov/pubmed/24369379
http://dx.doi.org/10.1093/brain/awt343
_version_ 1782302411846582272
author Giordano, Carla
Iommarini, Luisa
Giordano, Luca
Maresca, Alessandra
Pisano, Annalinda
Valentino, Maria Lucia
Caporali, Leonardo
Liguori, Rocco
Deceglie, Stefania
Roberti, Marina
Fanelli, Francesca
Fracasso, Flavio
Ross-Cisneros, Fred N.
D’Adamo, Pio
Hudson, Gavin
Pyle, Angela
Yu-Wai-Man, Patrick
Chinnery, Patrick F.
Zeviani, Massimo
Salomao, Solange R.
Berezovsky, Adriana
Belfort, Rubens
Ventura, Dora Fix
Moraes, Milton
Moraes Filho, Milton
Barboni, Piero
Sadun, Federico
De Negri, Annamaria
Sadun, Alfredo A.
Tancredi, Andrea
Mancini, Massimiliano
d’Amati, Giulia
Loguercio Polosa, Paola
Cantatore, Palmiro
Carelli, Valerio
author_facet Giordano, Carla
Iommarini, Luisa
Giordano, Luca
Maresca, Alessandra
Pisano, Annalinda
Valentino, Maria Lucia
Caporali, Leonardo
Liguori, Rocco
Deceglie, Stefania
Roberti, Marina
Fanelli, Francesca
Fracasso, Flavio
Ross-Cisneros, Fred N.
D’Adamo, Pio
Hudson, Gavin
Pyle, Angela
Yu-Wai-Man, Patrick
Chinnery, Patrick F.
Zeviani, Massimo
Salomao, Solange R.
Berezovsky, Adriana
Belfort, Rubens
Ventura, Dora Fix
Moraes, Milton
Moraes Filho, Milton
Barboni, Piero
Sadun, Federico
De Negri, Annamaria
Sadun, Alfredo A.
Tancredi, Andrea
Mancini, Massimiliano
d’Amati, Giulia
Loguercio Polosa, Paola
Cantatore, Palmiro
Carelli, Valerio
author_sort Giordano, Carla
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3914475
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-39144752014-02-05 Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy Giordano, Carla Iommarini, Luisa Giordano, Luca Maresca, Alessandra Pisano, Annalinda Valentino, Maria Lucia Caporali, Leonardo Liguori, Rocco Deceglie, Stefania Roberti, Marina Fanelli, Francesca Fracasso, Flavio Ross-Cisneros, Fred N. D’Adamo, Pio Hudson, Gavin Pyle, Angela Yu-Wai-Man, Patrick Chinnery, Patrick F. Zeviani, Massimo Salomao, Solange R. Berezovsky, Adriana Belfort, Rubens Ventura, Dora Fix Moraes, Milton Moraes Filho, Milton Barboni, Piero Sadun, Federico De Negri, Annamaria Sadun, Alfredo A. Tancredi, Andrea Mancini, Massimiliano d’Amati, Giulia Loguercio Polosa, Paola Cantatore, Palmiro Carelli, Valerio Brain Original Articles 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. Oxford University Press 2014-02 2013-12-24 /pmc/articles/PMC3914475/ /pubmed/24369379 http://dx.doi.org/10.1093/brain/awt343 Text en © The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Giordano, Carla
Iommarini, Luisa
Giordano, Luca
Maresca, Alessandra
Pisano, Annalinda
Valentino, Maria Lucia
Caporali, Leonardo
Liguori, Rocco
Deceglie, Stefania
Roberti, Marina
Fanelli, Francesca
Fracasso, Flavio
Ross-Cisneros, Fred N.
D’Adamo, Pio
Hudson, Gavin
Pyle, Angela
Yu-Wai-Man, Patrick
Chinnery, Patrick F.
Zeviani, Massimo
Salomao, Solange R.
Berezovsky, Adriana
Belfort, Rubens
Ventura, Dora Fix
Moraes, Milton
Moraes Filho, Milton
Barboni, Piero
Sadun, Federico
De Negri, Annamaria
Sadun, Alfredo A.
Tancredi, Andrea
Mancini, Massimiliano
d’Amati, Giulia
Loguercio Polosa, Paola
Cantatore, Palmiro
Carelli, Valerio
Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title_full Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title_fullStr Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title_full_unstemmed Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title_short Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
title_sort efficient mitochondrial biogenesis drives incomplete penetrance in leber’s hereditary optic neuropathy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914475/
https://www.ncbi.nlm.nih.gov/pubmed/24369379
http://dx.doi.org/10.1093/brain/awt343
work_keys_str_mv AT giordanocarla efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT iommariniluisa efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT giordanoluca efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT marescaalessandra efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT pisanoannalinda efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT valentinomarialucia efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT caporalileonardo efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT liguorirocco efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT decegliestefania efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT robertimarina efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT fanellifrancesca efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT fracassoflavio efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT rosscisnerosfredn efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT dadamopio efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT hudsongavin efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT pyleangela efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT yuwaimanpatrick efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT chinnerypatrickf efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT zevianimassimo efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT salomaosolanger efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT berezovskyadriana efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT belfortrubens efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT venturadorafix efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT moraesmilton efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT moraesfilhomilton efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT barbonipiero efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT sadunfederico efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT denegriannamaria efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT sadunalfredoa efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT tancrediandrea efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT mancinimassimiliano efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT damatigiulia efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT loguerciopolosapaola efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT cantatorepalmiro efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy
AT carellivalerio efficientmitochondrialbiogenesisdrivesincompletepenetranceinlebershereditaryopticneuropathy