Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance

Hudson, Gavin; Amati‐Bonneau, Patrizia; Blakely, Emma L.; Stewart, Joanna D.; He, Langping; Schaefer, Andrew M.; Griffiths, Philip G.; Ahlqvist, Kati J.; Suomalainen, Anu; Reynier, Pascal; McFarland, Robert; Turnbull, Douglass M.; Chinnery, Patrick F.; Taylor, Robert W.

doi:10.1093/brain/awm272

Cited by 375 publications

(288 citation statements)

References 51 publications

Supporting

Mentioning

266

Contrasting

Unclassified

Order By: Relevance

“…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: 78%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Resultssupporting

confidence: 78%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Zsurka and Kunz mutant MFN2 and OPA1 (80)(81)(82). Decreased copy numbers correlate with decreased respiratory enzyme activities, but it is not clear whether the respiratory deficiency plays the central role in the pathogenesis or rather the disturbed distribution of mitochondria within the neurons.…”

Section: Figmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

View full text Add to dashboard Cite

The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

show abstract

“…Nevertheless, the protein is expressed in all examined human tissues, explaining the accidental development of the so-called 'ADOA +' forms characterized by the association of the blindness with various neuromuscular disorders [17][18][19] or hearing loss [20,21]. The vulnerability of retinal ganglion cells and that of spiral ganglion cells in the inner ear [22] has been attributed to the impairment of ATP production as observed in fibroblasts [23,24] or skeletal muscle [25].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

View full text Add to dashboard Cite

The most frequent form of hereditary blindness, Autosomal Dominant Optic Atrophy (ADOA) is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca 2+ uptake (Fülöp et al.,PLoS One 2011). Therefore we studied mitochondrial Ca 2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell -inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca 2+ signals. The present data indicate that enhanced mitochondrial Ca 2+ uptake is a pathogenetic factor in the progress of ADOA.3

show abstract

Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance

Cited by 375 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

Mitochondrial involvement in neurodegenerative diseases

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Contact Info

Product

Resources

About