Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance.
Gavin Hudson,Patrizia Amati-Bonneau,Emma L. Blakely,Joanna Stewart,Langping He,Andrew M. Schaefer,Philip G. Griffiths,Kati J. Ahlqvist,Anu Suomalainen,Pascal Reynier,Robert McFarland,D.M. Turnbull,Patrick F. Chinnery,Robert W Taylor +13 more
TLDR
It is shown that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX), demonstrating the importance of OPA 1 in mtDNA maintenance, and implicates OPA2 in diseases associated with secondary defects of mtDNA.Abstract:
Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins--pol gamma, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.read more
Citations
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Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases
Hsiuchen Chen,David C. Chan +1 more
TL;DR: How mitochondrial dynamics is altered in these neurodegenerative diseases is reviewed and the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy are discussed.
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Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations.
Hsiuchen Chen,Marc Vermulst,Yun E. Wang,Anne Chomyn,Tomas A. Prolla,J. Michael McCaffery,David C. Chan +6 more
TL;DR: With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.
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Fusion and Fission: Interlinked Processes Critical for Mitochondrial Health
TL;DR: By enabling content mixing between mitochondria, fusion and fission serve to maintain a homogeneous and healthy mitochondrial population and lead to improvements in human health.
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Mitochondrial fragmentation in neurodegeneration
TL;DR: Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. as discussed by the authors showed that mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria.
Journal ArticleDOI
Mitochondrial Dynamics in Mammalian Health and Disease
TL;DR: Findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies have established mitochondrial dynamics as a consolidated area in cellular physiology.
References
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Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
Stephan Züchner,Stephan Züchner,Irina V. Mersiyanova,Maria Muglia,Nisrine Bissar-Tadmouri,Nisrine Bissar-Tadmouri,Julie M. Rochelle,Elena L. Dadali,Mario Zappia,Eva Nelis,Alessandra Patitucci,Jan Senderek,Yesim Parman,Oleg V. Evgrafov,Peter De Jonghe,Yuji Takahashi,Shoij Tsuji,Margaret A. Pericak-Vance,Aldo Quattrone,Esra Battologlu,Alexander V. Polyakov,Vincent Timmerman,J. Michael Schröder,Jeffery M. Vance +23 more
TL;DR: It is concluded that the primary gene mutated in CMT2A is MFN2, and seven large pedigrees affected with Charcot-Marie-Tooth neuropathy type 2A are concluded.
Journal ArticleDOI
Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.
Cécile Delettre,Guy Lenaers,Jean-Michel Griffoin,Nadine Gigarel,Corinne Lorenzo,Pascale Belenguer,Laetitia Pelloquin,J. Grosgeorge,Claude Turc-Carel,Eric Perret,Catherine Astarie-Dequeker,Laetitia Lasquellec,B. Arnaud,Bernard Ducommun,Josseline Kaplan,Christian P. Hamel +15 more
TL;DR: A nuclear gene, OPA1, is described here a nuclear gene that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.
Journal ArticleDOI
High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease.
Andreas Bender,Kim J. Krishnan,Christopher Morris,Geoffrey A. Taylor,Amy K. Reeve,Robert H. Perry,Evelyn Jaros,Joshua S Hersheson,Joanne Betts,Thomas Klopstock,Robert W. Taylor,Douglass M. Turnbull +11 more
TL;DR: It is shown that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA, suggesting that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.
Journal ArticleDOI
OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.
Christiane Alexander,Marcela Votruba,Marcela Votruba,Ulrike E.A. Pesch,Dawn L. Thiselton,Simone Mayer,Anthony T. Moore,Miguel Rodríguez,Ulrich Kellner,Beate Leo-Kottler,Georg Auburger,Shomi S. Bhattacharya,Bernd Wissinger +12 more
TL;DR: The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.
Journal ArticleDOI
Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction
TL;DR: It is shown that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction, suggesting a requirement for mitochondrial fusion, beyond maintenance of organelle morphology.
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Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.
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