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

Chunyan Liao; Neil Ashley; Alan Diot; Karl Morten; Kanchan Phadwal; Andrew Williams; Ian Fearnley; Lyndon Rosser; Jo Lowndes; Carl Fratter; David J P Ferguson; Laura Vay; Gerardine Quaghebeur; Isabella Moroni; Stefania Bianchi; Costanza Lamperti; Susan M Downes; Kamil S Sitarz; Padraig J Flannery; Janet Carver; Eszter Dombi; Daniel East; Matilde Laura; Mary M Reilly; Heather Mortiboys; Remko Prevo; Michelangelo Campanella; Matthew J Daniels; Massimo Zeviani; Patrick Yu-Wai-Man; Anna Katharina Simon; Marcela Votruba; Joanna Poulton

doi:10.1212/WNL.0000000000003491

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

Chunyan Liao, Neil Ashley, Alan Diot, Karl Morten, Kanchan Phadwal, Andrew Williams, Ian Fearnley, Lyndon Rosser, Jo Lowndes, Carl Fratter, David J P Ferguson, Laura Vay, Gerardine Quaghebeur, Isabella Moroni, Stefania Bianchi, Costanza Lamperti, Susan M Downes, Kamil S Sitarz, Padraig J Flannery, Janet CarverEszter Dombi, Daniel East, Matilde Laura, Mary M Reilly, Heather Mortiboys, Remko Prevo, Michelangelo Campanella, Matthew J Daniels, Massimo Zeviani, Patrick Yu-Wai-Man, Anna Katharina Simon, Marcela Votruba, Joanna Poulton

Division of Cardiovascular Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	131-142
Number of pages	12
Journal	Neurology
Volume	88
Issue number	2
Early online date	14 Dec 2016
DOIs	https://doi.org/10.1212/WNL.0000000000003491
Publication status	Published - 10 Jan 2017

Keywords

Antioxidants/pharmacology
Cells, Cultured
Cognition Disorders/etiology
DNA Mutational Analysis
DNA, Mitochondrial/genetics
Family Health
Female
Fibroblasts/drug effects
GTP Phosphohydrolases/genetics
Humans
Male
Membrane Potential, Mitochondrial/genetics
Mitochondrial Proteins/genetics
Mitophagy/genetics
Mutation/genetics
Optic Atrophy/complications
Pedigree
Protein Kinases/genetics
RNA, Small Interfering/genetics
Transfection
Ubiquinone/analogs & derivatives
Ubiquitin-Protein Ligases/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1212/WNL.0000000000003491Licence: CC BY

131.fullFinal published version, 3.51 MBLicence: CC BY

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Liao, C., Ashley, N., Diot, A., Morten, K., Phadwal, K., Williams, A., Fearnley, I., Rosser, L., Lowndes, J., Fratter, C., Ferguson, D. J. P., Vay, L., Quaghebeur, G., Moroni, I., Bianchi, S., Lamperti, C., Downes, S. M., Sitarz, K. S., Flannery, P. J., ... Poulton, J. (2017). Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. Neurology, 88(2), 131-142. https://doi.org/10.1212/WNL.0000000000003491

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title = "Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations",

abstract = "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.",

keywords = "Antioxidants/pharmacology, Cells, Cultured, Cognition Disorders/etiology, DNA Mutational Analysis, DNA, Mitochondrial/genetics, Family Health, Female, Fibroblasts/drug effects, GTP Phosphohydrolases/genetics, Humans, Male, Membrane Potential, Mitochondrial/genetics, Mitochondrial Proteins/genetics, Mitophagy/genetics, Mutation/genetics, Optic Atrophy/complications, Pedigree, Protein Kinases/genetics, RNA, Small Interfering/genetics, Transfection, Ubiquinone/analogs & derivatives, Ubiquitin-Protein Ligases/genetics",

author = "Chunyan Liao and Neil Ashley and Alan Diot and Karl Morten and Kanchan Phadwal and Andrew Williams and Ian Fearnley and Lyndon Rosser and Jo Lowndes and Carl Fratter and Ferguson, {David J P} and Laura Vay and Gerardine Quaghebeur and Isabella Moroni and Stefania Bianchi and Costanza Lamperti and Downes, {Susan M} and Sitarz, {Kamil S} and Flannery, {Padraig J} and Janet Carver and Eszter Dombi and Daniel East and Matilde Laura and Reilly, {Mary M} and Heather Mortiboys and Remko Prevo and Michelangelo Campanella and Daniels, {Matthew J} and Massimo Zeviani and Patrick Yu-Wai-Man and Simon, {Anna Katharina} and Marcela Votruba and Joanna Poulton",

note = "Copyright {\textcopyright} 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2017",

month = jan,

day = "10",

doi = "10.1212/WNL.0000000000003491",

language = "English",

volume = "88",

pages = "131--142",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams & Wilkins",

number = "2",

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Liao, C, Ashley, N, Diot, A, Morten, K, Phadwal, K, Williams, A, Fearnley, I, Rosser, L, Lowndes, J, Fratter, C, Ferguson, DJP, Vay, L, Quaghebeur, G, Moroni, I, Bianchi, S, Lamperti, C, Downes, SM, Sitarz, KS, Flannery, PJ, Carver, J, Dombi, E, East, D, Laura, M, Reilly, MM, Mortiboys, H, Prevo, R, Campanella, M, Daniels, MJ, Zeviani, M, Yu-Wai-Man, P, Simon, AK, Votruba, M & Poulton, J 2017, 'Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations', Neurology, vol. 88, no. 2, pp. 131-142. https://doi.org/10.1212/WNL.0000000000003491

TY - JOUR

T1 - Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

AU - Liao, Chunyan

AU - Ashley, Neil

AU - Diot, Alan

AU - Morten, Karl

AU - Phadwal, Kanchan

AU - Williams, Andrew

AU - Fearnley, Ian

AU - Rosser, Lyndon

AU - Lowndes, Jo

AU - Fratter, Carl

AU - Ferguson, David J P

AU - Vay, Laura

AU - Quaghebeur, Gerardine

AU - Moroni, Isabella

AU - Bianchi, Stefania

AU - Lamperti, Costanza

AU - Downes, Susan M

AU - Sitarz, Kamil S

AU - Flannery, Padraig J

AU - Carver, Janet

AU - Dombi, Eszter

AU - East, Daniel

AU - Laura, Matilde

AU - Reilly, Mary M

AU - Mortiboys, Heather

AU - Prevo, Remko

AU - Campanella, Michelangelo

AU - Daniels, Matthew J

AU - Zeviani, Massimo

AU - Yu-Wai-Man, Patrick

AU - Simon, Anna Katharina

AU - Votruba, Marcela

AU - Poulton, Joanna

PY - 2017/1/10

Y1 - 2017/1/10

N2 - 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.

AB - 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.

KW - Antioxidants/pharmacology

KW - Cells, Cultured

KW - Cognition Disorders/etiology

KW - DNA Mutational Analysis

KW - DNA, Mitochondrial/genetics

KW - Family Health

KW - Female

KW - Fibroblasts/drug effects

KW - GTP Phosphohydrolases/genetics

KW - Humans

KW - Male

KW - Membrane Potential, Mitochondrial/genetics

KW - Mitochondrial Proteins/genetics

KW - Mitophagy/genetics

KW - Mutation/genetics

KW - Optic Atrophy/complications

KW - Pedigree

KW - Protein Kinases/genetics

KW - RNA, Small Interfering/genetics

KW - Transfection

KW - Ubiquinone/analogs & derivatives

KW - Ubiquitin-Protein Ligases/genetics

U2 - 10.1212/WNL.0000000000003491

DO - 10.1212/WNL.0000000000003491

M3 - Article

C2 - 27974645

SN - 0028-3878

VL - 88

SP - 131

EP - 142

JO - Neurology

JF - Neurology

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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