OPA1 Deficiency Associated with Increased Autophagy in Retinal Ganglion Cells in a Murine Model of Dominant Optic Atrophy

White, Kathryn; Davies, Vanessa J.; Hogan, Vanessa; Piechota, Małgorzata; Nichols, Philip; Turnbull, Doug M.; Votruba, Marcela

doi:10.1167/iovs.08-2913

Cited by 85 publications

(55 citation statements)

References 29 publications

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“…Typically, uncoupling agents (FCCP or carbonyl cyanide m ‐chlorophenyl hydrazone, CCCP) promote mitochondrial permeabilization, leading to mitochondrial fragmentation and ultimately sequestration of damaged mitochondria by autophagosomes 45. It has been shown that mitochondria carrying deleterious mtDNA mutations can be selectively eliminated through mitophagy, and increased autophagy has recently been documented in RGCs in murine models of DOA 46, 47, 48…”

Section: Discussionmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

152

103

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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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Section: Discussionmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

152

103

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“…Differences in viability and tissue-specific effects have also been noted with mutations in the analogous C. elegans and Drosophila proteins (Kanazawa et al 2008;Yarosh et al 2008). Whereas homozygous mutations in mice are lethal, there are differences in the most severely affected stages and in heterozygous animals (Chen et al 2003;White et al 2009). Humans with disease-causing mutations in Mitofusins or Opa1 are generally heterozygous, but the diseases caused by these mutations are different: mutations in Opa1 cause optic atrophy through progressive loss of retinal ganglion cells, whereas mutations in Mfn2 cause a form of peripheral neuropathy (Charcot-Marie-Tooth disease CMT2A) (Chan 2012).…”

Section: Additional Roles Of Fusion Proteinsmentioning

confidence: 99%

Mechanisms of Mitochondrial Fission and Fusion

Bliek

Shen

Kawajiri

2013

Cold Spring Harbor Perspectives in Biology

638

459

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Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes. Here, we review what is known about these proteins and the processes that regulate their actions.

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“…It genetically interacts with the mitochondrial fission/fusion machinery and participates in a FOXO3a-mediated ROS defense pathway (Mei et al, 2009). Pink1 knockout results in respiratory dysfunction, ROS elevation (Wood-Kaczmar et al, 2008), and mitochondrial fission (Chu, 2010) (Fig. 3).…”

Section: Ros Affect Mitochondrial Networkmentioning

confidence: 98%

“…Overexpression of Fis1 leads to extensive fission of mitochondria and induces excessive mitochondrial autophagy (Gomes and Scorrano, 2008). Mitochondrial fusion protein OPA1 deficiency is associated with increased autophagy (White et al, 2009). Under starvation conditions the mitochondrial outer membrane serves as a resource of autophagosome and Mfn-2 plays an important role in regulating the starvation-induced autophagy (Hailey et al, 2010).…”

Section: Mitochondrial Morphological Changes In Mitophagy/autophagymentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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OPA1 Deficiency Associated with Increased Autophagy in Retinal Ganglion Cells in a Murine Model of Dominant Optic Atrophy

Cited by 85 publications

References 29 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Mechanisms of Mitochondrial Fission and Fusion

Mitochondrial network in the heart

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