Expression of the Opa1 Mitochondrial Protein in Retinal Ganglion Cells: Its Downregulation Causes Aggregation of the Mitochondrial Network

Kamei, Satomi; Chen-Kuo-Chang, Murielle; Cazevieille, Chantal; Lenaers, Guy; Olichon, Aurélien; Bélenguer, Pascale; Roussignol, Gautier; Renard, Nathalie; Eybalin, Michel; Michelin, Adeline; Delettre, Cécile; Brabet, Philippe; Hamel, Christian

doi:10.1167/iovs.03-1407

Cited by 62 publications

(33 citation statements)

References 51 publications

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“…Previous studies reported mitochondrial fragmentation in OPA1 knockdown RGCs. 23,37 However, morphological changes become apparent at longer post-transfection times (1 to 2 weeks), but not at 3 days after transfection. 37 Morphological changes coincided with induction of apoptosis and membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

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Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Bossy

et al. 2012

Cell Death Differ

101

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Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca 2 þ retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca 2 þ transients and corresponding reduction of NAD þ to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca 2 þ and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca 2 þ homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…23,37 However, morphological changes become apparent at longer post-transfection times (1 to 2 weeks), but not at 3 days after transfection. 37 Morphological changes coincided with induction of apoptosis and membrane depolarization. 23 All our experiments were performed no later than 3 days after transfection.…”

Section: Discussionmentioning

confidence: 99%

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Bossy

et al. 2012

Cell Death Differ

101

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“…22,28 Briefly, target-specific siRNA (AA(N19)UU) were designed (5'-aagucaucagucugagccagguu-3') corresponding to position c.1811-1833 of the mouse OPA1 open reading frame (GenBank accession number AY510274) and synthesized in duplex form (Dharmacond Research, CO, USA). The scramble siRNAs (5'-agguaguguaaucgccuuguu -3') were used as a negative control.…”

Section: Gene Silencing Strategymentioning

confidence: 99%

Characterization of Ca²⁺Signalling in Postnatal Mouse Retinal Ganglion Cells: Involvement of OPA1 in Ca²⁺Clearance

Dayanithi

Chen-Kuo-Chang

Viero

et al. 2010

Ophthalmic Genetics

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“…Retinal OPA1 is expressed in the soma and axons of the RGCs as well as in horizontal cells [17-19]. Although the specific functional role of OPA1 in these cells remains unknown, it has been shown that down-regulation of OPA1 causes mitochondrial fission, leading to cytochrome C release and apoptosis in HeLa cells, as well as induces aggregation of the mitochondrial network in purified RGCs [20-23]. Proteolytic processing of OPA1 has been observed during mitochondrial fission, although its significance remains poorly investigated [24-27].…”

Section: Introductionmentioning

confidence: 99%

Measuring Glutamate Receptor Activation-Induced Apoptotic Cell Death in Ischemic Rat Retina Using the TUNEL Assay

Kim²

2011

Methods in Molecular Biology

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Glutamate receptor activation-mediated excitotoxicity has been hypothesized to cause cell death in both acute and chronic neurodegenerative diseases including glaucoma. Although the precise mechanisms of ischemia-induced neuronal death are unknown, glutamate excitotoxicty-induced apoptotic cell death is considered to be an important component of postischemic damage in the retina. The blockade of apoptotic cell death induced by glutamate receptor activation provides strong evidence that glutamate excitotoxicity-induced apoptotic cell death may be a central mechanism of cell death in ischemic rat retina. We have shown that there is TUNEL-positive apoptotic cell death in the outer nuclear layer, inner nuclear layer and ganglion cell layer of the ischemic rat retina at 12 h.

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Expression of the Opa1 Mitochondrial Protein in Retinal Ganglion Cells: Its Downregulation Causes Aggregation of the Mitochondrial Network

Abstract: Results suggest that the level of expression and the mRNA isoforms do not underlie the vulnerability of RGCs to OPA1 mutations. However, aggregation of the mitochondrial network induced by the downregulation of Opa1 appears more frequent in RGCs than in control CGCs.

Cited by 62 publications

References 51 publications

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Characterization of Ca²⁺Signalling in Postnatal Mouse Retinal Ganglion Cells: Involvement of OPA1 in Ca²⁺Clearance

Measuring Glutamate Receptor Activation-Induced Apoptotic Cell Death in Ischemic Rat Retina Using the TUNEL Assay

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Expression of the Opa1 Mitochondrial Protein in Retinal Ganglion Cells: Its Downregulation Causes Aggregation of the Mitochondrial Network

Abstract: Results suggest that the level of expression and the mRNA isoforms do not underlie the vulnerability of RGCs to OPA1 mutations. However, aggregation of the mitochondrial network induced by the downregulation of Opa1 appears more frequent in RGCs than in control CGCs.

Cited by 62 publications

References 51 publications

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

Characterization of Ca2+Signalling in Postnatal Mouse Retinal Ganglion Cells: Involvement of OPA1 in Ca2+Clearance

Measuring Glutamate Receptor Activation-Induced Apoptotic Cell Death in Ischemic Rat Retina Using the TUNEL Assay

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Characterization of Ca²⁺Signalling in Postnatal Mouse Retinal Ganglion Cells: Involvement of OPA1 in Ca²⁺Clearance