OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution

Elachouri, Ghizlane; Vidoni, Sara; Zanna, Claudia; Pattyn, Alexandre; Boukhaddaoui, Hassan; Gaget, Karen; Yu‐Wai‐Man, Patrick; Gasparre, Giuseppe; Sarzi, Emmanuelle; Delettre, Cécile; Olichon, Aurélien; Loiseau, Dominique; Reynier, Pascal; Chinnery, Patrick F.; Rötig, Agnès; Carelli, Valerio; Hamel, Christian; Rugolo, Michela; Lenaers, Guy

doi:10.1101/gr.108696.110

Cited by 206 publications

(148 citation statements)

References 43 publications

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“…Recently, mitochondrial fusion and fission factors have been shown to influence the organization of mtDNA nucleoids. 41,52,53 In the present study, we found that Mic60/Mitofilin has an important role in the maintaining of mtDNA nucleoid organization and function in mammals ( Figures 5B and 6a). Thus, an important question is how Mic60/Mitofilin regulates the distribution and size of mtDNA nucleoids?…”

Section: Discussionsupporting

confidence: 61%

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

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The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins.Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. Mitochondria have a key role in oxidative phosphorylation and related cellular metabolism, in energy conversion, in programmed cell death, in cell growth and in diseases. Mitochondrial outer and inner membranes strongly differ in architecture and functions. The mitochondrial outer membrane forms a barrier to cytosol, and contains channels and the translocases of outer membrane, which is the main protein entry gate of mitochondria. 1,2 In contrast, the mitochondrial inner membrane consists of two morphologically distinct regions: the inner boundary membrane is in close proximity to the outer membrane and the cristae membranes that are large tubular invaginations. [3][4][5][6][7][8] The mitochondrial inner boundary and cristae membrane are physically separated by cristae junctions, which are narrow tubular or slot-like structure. 4,9 The mitochondrial cristae are arranged in regular arrays and are the main sites of ATP production in the mitochondria, but the molecules that are associated with the maintenance of cristae architecture still remain elusive. Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five s...

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Section: Discussionsupporting

confidence: 61%

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

et al. 2015

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“…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. The involvement of specific isoforms of OPA1 in mtDNA maintenance and nucleoid organization has been recently proposed 23. However, the mechanism linking specific OPA1 mutations to mtDNA maintenance and instability remains mostly unclear.…”

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confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

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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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“…54 Small hydrophobic peptide fragments from cleaved OPA1 may also contribute to mtDNA nucleoid attachment to the inner mitochondrial membrane, promoting mtDNA replication and distribution. 85 Disrupted mtDNA distribution, or cristae structure, is predicted to have secondary impacts on oxidative phosphorylation due to either inadequate mtDNA transcription or lack of inner membrane surface area for oxidative phosphorylation complex anchoring. It has been reported that decreased oxidative phosphorylation capacity in ADOA patients with OPA1 mutations correlates with relatively poor visual acuities, while related mutation carriers with normal vision appeared to have relatively preserved oxidative phosphorylation function.…”

Section: Mitochondrial Diseases and Optic Neuropathiesmentioning

confidence: 99%

Mitochondrial disorders and the eye

Bergen

Chakrabarti

O'Neill

et al. 2011

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Abstract:The clinical significance of disturbed mitochondrial function in the eye has emerged since mitochondrial DNA (mtDNA) mutation was described in Leber's hereditary optic neuropathy. The spectrum of mitochondrial dysfunction has become apparent through increased understanding of the contribution of nuclear and somatic mtDNA mutations to mitochondrial dynamics and function. Common ophthalmic manifestations of mitochondrial dysfunction include optic atrophy, pigmentary retinopathy, and ophthalmoplegia. The majority of patients with ocular manifestations of mitochondrial disease also have variable central and peripheral nervous system involvement. Mitochondrial dysfunction has recently been associated with agerelated retinal disease including macular degeneration and glaucoma. Therefore, therapeutic targets directed at promoting mitochondrial biogenesis and function offer a potential to both preserve retinal function and attenuate neurodegenerative processes.

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OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution

Cited by 206 publications

References 43 publications

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Mitochondrial disorders and the eye

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