Regulation of mitochondrial morphology through proteolytic cleavage of OPA1.

doi:10.1038/SJ.EMBOJ.7601184

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Regulation of mitochondrial morphology through proteolytic cleavage of OPA1.

Journal Article•DOI•

Regulation of mitochondrial morphology through proteolytic cleavage of OPA1.

Naotada Ishihara¹, Yuu Fujita¹, Toshihiko Oka¹, Katsuyoshi Mihara¹•Institutions (1)

Kyushu University¹

12 Jul 2006-The EMBO Journal (European Molecular Biology Organization)-Vol. 25, Iss: 13, pp 2966-2977

TL;DR: M mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ‐dependent manner through proteolytic cleavage of Mgm1, the yeast homolog of O PA1.

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Abstract: The dynamin-like GTPase OPA1, a causal gene product of human dominant optic atrophy, functions in mitochondrial fusion and inner membrane remodeling. It has several splice variants and even a single variant is found as several processed forms, although their functional significance is unknown. In yeast, mitochondrial rhomboid protease regulates mitochondrial function and morphology through proteolytic cleavage of Mgm1, the yeast homolog of OPA1. We demonstrate that OPA1 variants are synthesized with a bipartite-type mitochondrial targeting sequence. During import, the matrix-targeting signal is removed and processed forms (L-isoforms) are anchored to the inner membrane in type I topology. L-isoforms undergo further processing in the matrix to produce S-isoforms. Knockdown of OPA1 induced mitochondrial fragmentation, whose network morphology was recovered by expression of L-isoform but not S-isoform, indicating that only L-isoform is fusion-competent. Dissipation of membrane potential, expression of m-AAA protease paraplegin, or induction of apoptosis stimulated this processing along with the mitochondrial fragmentation. Thus, mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ-dependent manner.

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Journal Article•DOI•

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

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Gilad Twig¹, Alvaro A. Elorza¹, Anthony J.A. Molina², Anthony J.A. Molina¹, Hibo Mohamed¹, Jakob D. Wikstrom¹, Gil Walzer¹, Linsey Stiles¹, Sarah E. Haigh¹, Steve Katz¹, Guy Las¹, Joseph Alroy¹, Min Wu³, Bénédicte F. Py⁴, Junying Yuan⁴, Jude T. Deeney², Barbara E. Corkey², Orian S. Shirihai¹ - Show less +14 more•Institutions (4)

Tufts University¹, Boston University², Seahorse Bioscience³, Harvard University⁴

23 Jan 2008-The EMBO Journal

TL;DR: Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagic.

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Abstract: Accumulation of depolarized mitochondria within β-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψm) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose Δψm and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.

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2,642 citations

Cites background from "Regulation of mitochondrial morphol..."

...Recently, a protonophore-induced complete collapse of Dcm of the entire cell mitochondria was shown to trigger proteolytic cleavage or degradation of OPA1 long (l-)isoforms (Griparic et al, 2004; Duvezin-Caubet et al, 2006; Ishihara et al, 2006; Song et al, 2007)....
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...…(Dcm) using pharmacologic uncouplers resulted in extensive network fragmentation, degradation of the cellular Optic Atrophy-1 protein (OPA1, a fusion protein) and the inhibition of fusion (Legros et al, 2002; Meeusen et al, 2004; Duvezin-Caubet et al, 2006; Ishihara et al, 2006; Song et al, 2007)....
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...Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run’ pattern....
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Journal Article•DOI•

Mitochondrial fusion and fission in cell life and death

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Benedikt Westermann¹•Institutions (1)

University of Bayreuth¹

01 Dec 2010-Nature Reviews Molecular Cell Biology

TL;DR: The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion andfission of a double membrane-bound organelle.

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Abstract: Mitochondria are dynamic organelles that constantly fuse and divide. These processes (collectively termed mitochondrial dynamics) are important for mitochondrial inheritance and for the maintenance of mitochondrial functions. The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion and fission of a double membrane-bound organelle. Mitochondrial dynamics was recently recognized as an important constituent of cellular quality control. Defects have detrimental consequences on bioenergetic supply and contribute to the pathogenesis of neurodegenerative diseases. These findings open exciting new directions to explore mitochondrial biology.

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1,637 citations

Journal Article•DOI•

Functions and dysfunctions of mitochondrial dynamics.

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Scott A. Detmer¹, David C. Chan¹•Institutions (1)

California Institute of Technology¹

01 Nov 2007-Nature Reviews Molecular Cell Biology

TL;DR: The molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function are reviewed and how defects in mitochondrial dynamics might cause neuronal disease is explored.

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Abstract: Recent findings have sparked renewed appreciation for the remarkably dynamic nature of mitochondria. These organelles constantly fuse and divide, and are actively transported to specific subcellular locations. These dynamic processes are essential for mammalian development, and defects lead to neurodegenerative disease. But what are the molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function? We review these issues and explore how defects in mitochondrial dynamics might cause neuronal disease.

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1,234 citations

Cites background from "Regulation of mitochondrial morphol..."

...The mechanistic link between membrane potential and fusion remains to be resolved, but one factor appears to be the dependence of post-translational processing of OPA1 on the membrane potentia...
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Journal Article•DOI•

Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin

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Atsushi Tanaka¹, Megan M. Cleland¹, Shan-Shan Xu², Derek P. Narendra¹, Der-Fen Suen¹, Mariusz Karbowski², Richard J. Youle¹ - Show less +3 more•Institutions (2)

National Institutes of Health¹, University of Maryland, Baltimore²

27 Dec 2010-Journal of Cell Biology

TL;DR: The Parkin ubiquitin ligase marks the mitofusins Mfn1 and Mfn2 for proteasome-dependent degradation, promoting disposal of damaged mitochondria by preventing their fusion with healthy organelles.

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Abstract: Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson’s disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.

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1,188 citations

Cites background from "Regulation of mitochondrial morphol..."

...We found that upon mitochondrial depolarization, Opa1 cleavage (Ishihara et al., 2006; Griparic et al., 2007) occurs more rapidly than mitofusin degradation (unpublished data), which suggests that the elimination of mitofusins does not cause the initial mitochondrial fragmentation but might delay…...
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...None of the other mitochondrial proteins examined displayed a reduction in protein levels, whereas Opa1 was cleaved as previously described (Ishihara et al., 2006; Griparic et al., 2007)....
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Journal Article•DOI•

Mitochondrial dynamics and apoptosis

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Der-Fen Suen¹, Kristi L. Norris¹, Richard J. Youle¹•Institutions (1)

National Institutes of Health¹

15 Jun 2008-Genes & Development

TL;DR: This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.

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Abstract: In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.

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1,156 citations

Cites background from "Regulation of mitochondrial morphol..."

...2006), parapalegin (Ishihara et al. 2006), and Yme1 (Griparic et al....
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...…across the inner mitochondrial membrane is reduced, suggesting that OPA1 processing and thus its activity could be regulated to coordinate the energetic state of mitochondria with organelle morphology (Griparic et al. 2004; Duvezin-Caubet et al. 2006; Ishihara et al. 2006; Meeusen et al. 2006)....
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...OPA1 cleavage is accelerated when the electrochemical potential across the inner mitochondrial membrane is reduced, suggesting that OPA1 processing and thus its activity could be regulated to coordinate the energetic state of mitochondria with organelle morphology (Griparic et al. 2004; Duvezin-Caubet et al. 2006; Ishihara et al. 2006; Meeusen et al. 2006)....
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...A variety of proteases including members of the rhomboid family (Herlan et al. 2003; McQuibban et al. 2003; Sesaki et al. 2003; Cipolat et al. 2006), parapalegin (Ishihara et al. 2006), and Yme1 (Griparic et al. 2007; Song et al. 2007) have been implicated in OPA1 processing....
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...Cleaved forms of OPA1 are more loosely attached to the inner mitochondrial membrane than long forms that retain a hydrophobic domain (Ishihara et al. 2006)....
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References

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Journal Article•DOI•

The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis.

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Stephan Frank¹, Brigitte Gaume, Elke S. Bergmann-Leitner, Wolfgang W. Leitner, Everett G. Robert, Frédéric Catez, Carolyn L. Smith¹, Richard J. Youle - Show less +4 more•Institutions (1)

National Institutes of Health¹

01 Oct 2001-Developmental Cell

TL;DR: In healthy cells, fusion and fission events participate in regulating mitochondrial morphology and inhibition of Drp1 blocks cell death, implicating mitochondrial fission as an important step in apoptosis.

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1,665 citations

"Regulation of mitochondrial morphol..." refers background in this paper

...Knockdown of OPA1 induced mitochondrial fragmentation, whose network morphology was recovered by expression of L-isoform but not S-isoform, indicating that only L-isoform is fusion-competent....
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...Mitochondria have a central role in apoptosis, and mitochondrial fragmentation activates the progression of apoptosis and increases sensitivity to proapoptotic stimuli (Frank et al, 2001; Lee et al, 2004)....
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...In this context, mitochondrial fragmentation is intimately correlated to the progression of apoptosis (Frank et al, 2001; Lee et al, 2004; Sugioka et al, 2004)....
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...Scale bar: 10mm. (F) The number of cells with highly elongated and enriched mitochondria, filamentous-network, intermediate, or completely fragmented mitochondrial structures in (E) were counted and are shown as a percentage....
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...Proapoptotic stimuli also activate mitochondrial fission and, conversely, inhibit mitochondrial fusion, resulting in mitochondrial fragmentation (Frank et al, 2001; Karbowski and Youle, 2003)....
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Journal Article•DOI•

Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.

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Cécile Delettre¹, Guy Lenaers², Jean-Michel Griffoin, Nadine Gigarel³, Corinne Lorenzo², Pascale Belenguer², Laetitia Pelloquin², J. Grosgeorge⁴, Claude Turc-Carel⁴, Eric Perret, Catherine Astarie-Dequeker⁴, Laetitia Lasquellec, B. Arnaud, Bernard Ducommun², Josseline Kaplan³, Christian P. Hamel - Show less +12 more•Institutions (4)

French Institute of Health and Medical Research¹, Paul Sabatier University², Necker-Enfants Malades Hospital³, Centre national de la recherche scientifique⁴

01 Oct 2000-Nature Genetics

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.

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Abstract: Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy occurring in 1 in 50,000 individuals that features progressive loss in visual acuity leading, in many cases, to legal blindness. Phenotypic variations and loss of retinal ganglion cells, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment. The OPA1 gene has been localized to 3q28-q29 (refs 13-19). We describe here a nuclear gene, OPA1, that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria. We found four different OPA1 mutations, including frameshift and missense mutations, to segregate with the disease, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.

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1,375 citations

"Regulation of mitochondrial morphol..." refers background in this paper

...OPA1 is a causal gene product of autosomal dominant optic atrophy, which features a progressive loss of retinal ganglion cells that leads to legal blindness (Alexander et al, 2000; Delettre et al, 2000)....
[...]
...The EMBO Journal (2006) 25, 2966–2977. doi:10.1038/ sj.emboj.7601184; Published online 15 June 2006 Subject Categories: membranes & transport Keywords: AAA-protease; mitochondrial fission; mitochondrial fusion; OPA1; rhomboid protease...
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Journal Article•DOI•

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

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Christiane Alexander¹, Marcela Votruba¹, Marcela Votruba², Ulrike E.A. Pesch³, Dawn L. Thiselton¹, Simone Mayer³, Anthony T. Moore², Miguel Rodríguez, Ulrich Kellner, Beate Leo-Kottler³, Georg Auburger⁴, Shomi S. Bhattacharya¹, Bernd Wissinger³ - Show less +9 more•Institutions (4)

University College London¹, Moorfields Eye Hospital², University of Tübingen³, University of Düsseldorf⁴

01 Oct 2000-Nature Genetics

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.

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Abstract: Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. 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.

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1,244 citations

"Regulation of mitochondrial morphol..." refers background in this paper

...OPA1 is a causal gene product of autosomal dominant optic atrophy, which features a progressive loss of retinal ganglion cells that leads to legal blindness (Alexander et al, 2000; Delettre et al, 2000)....
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Journal Article•DOI•

Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction

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Hsiuchen Chen¹, Anne Chomyn¹, David C. Chan¹•Institutions (1)

California Institute of Technology¹

15 Jul 2005-Journal of Biological Chemistry

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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1,244 citations

"Regulation of mitochondrial morphol..." refers background or result in this paper

...Knockdown of human OPA1 in HeLa cells by small interference RNA (siRNA) induced mitochondrial fragmentation through inhibition of mitochondrial fusion, confirming the previous report (Figure 4A and B) (Griparic et al, 2004; Chen et al, 2005)....
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...As OPA1 is strictly required for mitochondrial fusion (Chen et al, 2005), we then examined mitochondrial fusion activity for the mitochondria harboring various OPA1 constructs....
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...As confirming these results, mitochondria in the S-isoformexpressing cells exhibited small fragmented morphology (see AIF-230 in Supplementary Figure S4), resembling that of the fusion-defect mitochondria in OPA1-depleted cells (Chen et al, 2005)....
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Journal Article•DOI•

OPA1 requires mitofusin 1 to promote mitochondrial fusion

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Sara Cipolat, Olga Martins de Brito, Barbara Dal Zilio, Luca Scorrano

09 Nov 2004-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: A genetic analysis proved that OPA1 was unable to tubulate and fuse mitochondria lacking the outer membrane mitofusin 1 but not mit ofusin 2, and revealed a specific functional difference between mitofUsin 1 and 2.

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Abstract: The regulated equilibrium between mitochondrial fusion and fission is essential to maintain integrity of the organelle. Mechanisms of mitochondrial fusion are largely uncharacterized in mammalian cells. It is unclear whether OPA1, a dynamin-related protein of the inner membrane mutated in autosomal dominant optic atrophy, participates in fusion or fission. OPA1 promoted the formation of a branched network of elongated mitochondria, requiring the integrity of both its GTPase and C-terminal coiled-coil domain. Stable reduction of OPA1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. Levels of OPA1 did not affect mitochondrial docking, but they correlated with the extent of fusion as measured by polyethylene glycol mitochondrial fusion assays. A genetic analysis proved that OPA1 was unable to tubulate and fuse mitochondria lacking the outer membrane mitofusin 1 but not mitofusin 2. Our data show that OPA1 functionally requires mitofusin 1 to regulate mitochondrial fusion and reveal a specific functional difference between mitofusin 1 and 2.

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1,110 citations

"Regulation of mitochondrial morphol..." refers background in this paper

...Similarly, OPA1 requires Mfn1 of the outer membrane to promote mitochondrial fusion in mammalian cells (Cipolat et al, 2004), although the functional homologue of yeast Ugo1 is not known....
[...]
...The EMBO Journal (2006) 25, 2966–2977. doi:10.1038/ sj.emboj.7601184; Published online 15 June 2006 Subject Categories: membranes & transport Keywords: AAA-protease; mitochondrial fission; mitochondrial fusion; OPA1; rhomboid protease...
[...]
...In mammalian cells, exogenous expression of OPA1 affects mitochondrial morphology, and depletion of OPA1 by RNA interference (RNAi) induces mitochondrial fragmentation with aberrant inner membrane structures (Misaka et al, 2002; Olichon et al, 2003; Cipolat et al, 2004; Griparic et al, 2004)....
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