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Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitiv...

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Autores principales: Liao, Chunyan, Ashley, Neil, Diot, Alan, Morten, Karl, Phadwal, Kanchan, Williams, Andrew, Fearnley, Ian, Rosser, Lyndon, Lowndes, Jo, Fratter, Carl, Ferguson, David J.P., Vay, Laura, Quaghebeur, Gerardine, Moroni, Isabella, Bianchi, Stefania, Lamperti, Costanza, Downes, Susan M., Sitarz, Kamil S., Flannery, Padraig J., Carver, Janet, Dombi, Eszter, East, Daniel, Laura, Matilde, Reilly, Mary M., Mortiboys, Heather, Prevo, Remko, Campanella, Michelangelo, Daniels, Matthew J., Zeviani, Massimo, Yu-Wai-Man, Patrick, Simon, Anna Katharina, Votruba, Marcela, Poulton, Joanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224718/
https://www.ncbi.nlm.nih.gov/pubmed/27974645
http://dx.doi.org/10.1212/WNL.0000000000003491
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author Liao, Chunyan
Ashley, Neil
Diot, Alan
Morten, Karl
Phadwal, Kanchan
Williams, Andrew
Fearnley, Ian
Rosser, Lyndon
Lowndes, Jo
Fratter, Carl
Ferguson, David J.P.
Vay, Laura
Quaghebeur, Gerardine
Moroni, Isabella
Bianchi, Stefania
Lamperti, Costanza
Downes, Susan M.
Sitarz, Kamil S.
Flannery, Padraig J.
Carver, Janet
Dombi, Eszter
East, Daniel
Laura, Matilde
Reilly, Mary M.
Mortiboys, Heather
Prevo, Remko
Campanella, Michelangelo
Daniels, Matthew J.
Zeviani, Massimo
Yu-Wai-Man, Patrick
Simon, Anna Katharina
Votruba, Marcela
Poulton, Joanna
author_facet Liao, Chunyan
Ashley, Neil
Diot, Alan
Morten, Karl
Phadwal, Kanchan
Williams, Andrew
Fearnley, Ian
Rosser, Lyndon
Lowndes, Jo
Fratter, Carl
Ferguson, David J.P.
Vay, Laura
Quaghebeur, Gerardine
Moroni, Isabella
Bianchi, Stefania
Lamperti, Costanza
Downes, Susan M.
Sitarz, Kamil S.
Flannery, Padraig J.
Carver, Janet
Dombi, Eszter
East, Daniel
Laura, Matilde
Reilly, Mary M.
Mortiboys, Heather
Prevo, Remko
Campanella, Michelangelo
Daniels, Matthew J.
Zeviani, Massimo
Yu-Wai-Man, Patrick
Simon, Anna Katharina
Votruba, Marcela
Poulton, Joanna
author_sort Liao, Chunyan
collection PubMed
description OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. RESULTS: Fibroblasts from 3 biallelic OPA1(−/−) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. CONCLUSIONS: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion.
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spelling pubmed-52247182017-01-17 Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations Liao, Chunyan Ashley, Neil Diot, Alan Morten, Karl Phadwal, Kanchan Williams, Andrew Fearnley, Ian Rosser, Lyndon Lowndes, Jo Fratter, Carl Ferguson, David J.P. Vay, Laura Quaghebeur, Gerardine Moroni, Isabella Bianchi, Stefania Lamperti, Costanza Downes, Susan M. Sitarz, Kamil S. Flannery, Padraig J. Carver, Janet Dombi, Eszter East, Daniel Laura, Matilde Reilly, Mary M. Mortiboys, Heather Prevo, Remko Campanella, Michelangelo Daniels, Matthew J. Zeviani, Massimo Yu-Wai-Man, Patrick Simon, Anna Katharina Votruba, Marcela Poulton, Joanna Neurology Article OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. RESULTS: Fibroblasts from 3 biallelic OPA1(−/−) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. CONCLUSIONS: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion. Lippincott Williams & Wilkins 2017-01-10 /pmc/articles/PMC5224718/ /pubmed/27974645 http://dx.doi.org/10.1212/WNL.0000000000003491 Text en Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Licence 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Liao, Chunyan
Ashley, Neil
Diot, Alan
Morten, Karl
Phadwal, Kanchan
Williams, Andrew
Fearnley, Ian
Rosser, Lyndon
Lowndes, Jo
Fratter, Carl
Ferguson, David J.P.
Vay, Laura
Quaghebeur, Gerardine
Moroni, Isabella
Bianchi, Stefania
Lamperti, Costanza
Downes, Susan M.
Sitarz, Kamil S.
Flannery, Padraig J.
Carver, Janet
Dombi, Eszter
East, Daniel
Laura, Matilde
Reilly, Mary M.
Mortiboys, Heather
Prevo, Remko
Campanella, Michelangelo
Daniels, Matthew J.
Zeviani, Massimo
Yu-Wai-Man, Patrick
Simon, Anna Katharina
Votruba, Marcela
Poulton, Joanna
Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title_full Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title_fullStr Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title_full_unstemmed Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title_short Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations
title_sort dysregulated mitophagy and mitochondrial organization in optic atrophy due to opa1 mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224718/
https://www.ncbi.nlm.nih.gov/pubmed/27974645
http://dx.doi.org/10.1212/WNL.0000000000003491
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