OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes

Amati‐Bonneau, Patrizia; Valentino, Maria Lucia; Reynier, Pascal; Gallardo, M. Esther; Börnstein, Belén; Boissière, Anne; Campos, Yolanda; Rivera, Humberto Fernando Cantú; Aleja, Jesús González de la; Carroccia, Rosanna; Iommarini, Luisa; Labauge, Pierre; Figarella‐Branger, Dominique; Marcorelles, Pascale; Furby, Alain; Beauvais, Katell; Letournel, Franck; Liguori, Rocco; Morgia, Chiara La; Montagna, Pasquale; Liguori, Maria; Zanna, Claudia; Rugolo, Michela; Cossarizza, Andrea; Wissinger, Bernd; Verny, Christophe; Schwarzenbacher, Robert; Martín, Miguel A.; Arenas, Joaquı́n; Ayuso, Carmen; Garesse, Rafael; Lenaers, Guy; Bonneau, Dominique; Carelli, Valerio

doi:10.1093/brain/awm298

Cited by 455 publications

(386 citation statements)

References 51 publications

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“…Despite this clear functional deficit, we did not detect overt changes in the morphology of the mitochondria or cristae when assessed by TEM at either early or late time points (DIV25/45/85, not shown) and illustrated here at DIV65 (Fig 4E). mtDNA analysis did not reveal any deletions in the patient‐derived neurons (Fig 5) as previously reported in skeletal muscle 5, 6. Thus, reduced OPA1 protein levels in iPSC‐derived neurons cause a delayed defect in oxidative phosphorylation, which is most likely at the level of complex I.…”

Section: Resultssupporting

confidence: 79%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

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ObjectiveDefective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)‐based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism.MethodsiPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long‐range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants.ResultsOPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation.InterpretationOPA1 levels maintain oxidative phosphorylation in iPSC‐derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1‐mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. Ann Neurol 2018;83:915–925

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Section: Resultssupporting

confidence: 79%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

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“…Long‐range polymerase chain reaction (PCR) on mtDNA was performed to screen for the presence of mtDNA deletions as previously described 17. Briefly, the set of primers used is as follows: F3485‐3519 and R14820‐14786 (wild‐type mtDNA fragment of 11.335bp), F5459‐5493 and R735‐701 (wild‐type mtDNA fragment of 11.845bp).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, a mtDNA fragment (nt 4625–4714) and a nuclear DNA fragment (FasL gene) were coamplified by multiplex PCR. PCR reaction conditions, primers, and probes were as previously detailed 17. A standard curve for mtDNA and nDNA was generated using serial known dilutions of a vector (kindly provided by Genemore, Modena, Italy) in which the regions used as template for the 2 amplifications were cloned tail to tail, to have a ratio of 1:1 of the reference molecules.…”

Section: Methodsmentioning

confidence: 99%

“…We and others have recently added OPA1 to the list of genes responsible for accumulation of multiple mtDNA deletions 16, 17. Whereas most of the OPA1 mutations cause nonsyndromic, dominant optic atrophy (DOA), Kjer type (Online Mendelian Inheritance in Man database #165500; see www.mitodyn.org),18, 19, 20 a set of missense mutations in the guanosine triphosphatase (GTPase) domain, are associated with a DOA‐plus syndrome, which can variably include, in addition to optic atrophy, severe sensorineural deafness, cerebellar ataxia, axonal sensorimotor polyneuropathy, and CPEO/mitochondrial myopathy with multiple mtDNA deletions 16, 17, 21.…”

mentioning

confidence: 99%

“…Whereas most of the OPA1 mutations cause nonsyndromic, dominant optic atrophy (DOA), Kjer type (Online Mendelian Inheritance in Man database #165500; see www.mitodyn.org),18, 19, 20 a set of missense mutations in the guanosine triphosphatase (GTPase) domain, are associated with a DOA‐plus syndrome, which can variably include, in addition to optic atrophy, severe sensorineural deafness, cerebellar ataxia, axonal sensorimotor polyneuropathy, and CPEO/mitochondrial myopathy with multiple mtDNA deletions 16, 17, 21. In contrast to the previous gene products, which are directly linked to mtDNA replication and nucleotide balance, the OPA1 protein is a dynamin‐related GTPase involved in mitochondrial fusion, morphology, and apoptosis 22.…”

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confidence: 99%

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Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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Progressive External Ophthalmoplegia and Vision and Hearing Loss in a Patient With Mutations in POLG2 and OPA1

Ferraris¹,

Clark²,

Garelli³

et al. 2008

Arch Neurol

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To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase ␥ (POLG2) and a mutation in the OPA1 gene.Design: Clinical examination and morphological, biochemical, and molecular analyses.Setting: Tertiary care university hospitals and molecular genetics and scientific computing laboratory.Patient: A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal.Results: A muscle biopsy specimen showed scattered intensely succinate dehydrogenase-positive and cytochrome-c oxidase-negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those in POLG (polymerase ␥ gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C). Conclusion:Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.

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OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes

Cited by 455 publications

References 51 publications

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Progressive External Ophthalmoplegia and Vision and Hearing Loss in a Patient With Mutations in POLG2 and OPA1

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