OPA1 (dys)functions

doi:10.1016/j.semcdb.2009.12.012

Seminars in Cell & Developmental Biology

Volume 21, Issue 6, August 2010, Pages 593-598

https://doi.org/10.1016/j.semcdb.2009.12.012 Get rights and content

Abstract

Mitochondrial morphology varies according to cell type and cellular context from an interconnected filamentous network to isolated dots. This morphological plasticity depends on mitochondrial dynamics, a balance between antagonistic forces of fission and fusion. DRP1 and FIS1 control mitochondrial outer membrane fission and Mitofusins its fusion. This review focuses on OPA1, one of the few known actors of inner membrane dynamics, whose mutations provoke an optic neuropathy. Since its first identification in 2000 the characterization of the functions of OPA1 has made rapid progress thus providing numerous clues to unravel the pathogenetic mechanisms of ADOA-1.

Introduction

Mitochondria form a highly dynamic reticulum which morphology varies according to cell types and contexts and depends on continuous fission and fusion of both mitochondrial outer (OM) and inner membranes (IM). In the past decade, genetic screens in yeast led to the identification of several evolutionarily conserved proteins essential for the maintenance of mitochondrial morphology. In mammals, FIS1 and DRP1 drive mitochondrial fission whereas fusion involves the OM proteins Mitofusin-1 and -2 (MFN1 and MFN2), and the IM-located OPA1 [1]. Accumulating data show the impact of mitochondrial dynamics on mitochondrial functions and on the physiology of the cell [2]. Furthermore these processes are essential for mammalian development and are affected in neurodegenerative diseases.

In this review, we will focus on OPA1 and discuss to which extent the recent progresses in elucidating the different functions of this dynamin could help understanding the pathological mechanisms of type 1 optic atrophy (ADOA-1 OMIM 165500). ADOA-1 is a neurological disease caused by mutations of OPA1, that affects retinal ganglion cells (RGC) whose axons form the optic nerve, and leads to reduced visual acuity and possibly to blindness [3].

Section snippets

OPA1 expression

The OPA1 gene encodes a mitochondrial protein localized in the inter-membrane space (IMS) and associated to mitochondrial membranes [4], [5], [6], [7]. OPA1, and its yeast orthologues Mgm1p in Saccharomyces cerevisiae and Msp1p in Schizosaccharomyces pombe, belongs to the dynamins’ family [8], [9], [10], [11]; with which it shares three conserved regions: a GTPase domain, a middle domain and a carboxy-terminal coiled-coil domain (CC-II) also called GTPase effector domain (GED) (Fig. 1). The

OPA1, mitochondrial fusion

Loss of function of OPA1 by RNAi or gene knockout, or of Mgm1p and Msp1p, causes fragmentation of the tubular mitochondrial reticulum [5], [23], [24], [25], [26]. Conversely, over-production of this protein promotes mitochondrial elongation in cells where mitochondria are punctuated [4], [27]. Surprisingly, over-expression of the dynamin in cells with tubular mitochondria causes mitochondrial fragmentation [5], [28]. However, such cells still possess a normal mitochondrial fusion activity [27],

OPA1, apoptosis

In addition to mitochondrial fragmentation, downregulation of OPA1, or expression of pathogenic mutants, increases cell sensitivity to spontaneous and induced apoptosis [25], [30], [39]. These observations lead to propose that OPA1 functions as an anti-apoptotic protein providing link between mitochondrial dynamics and apoptosis, a subject of extensive debate. Indeed, over-expression of OPA1, by inhibiting cytochrome c release, protects cells from apoptosis induced by intrinsic stimuli [46].

OPA1, mtDNA maintenance

While Mgm1p has been identified thanks to its role in mtDNA maintenance, it is only recently that OPA1 has been linked to mtDNA stability. Missense mutations in OPA1 cause accumulation of multiple deletions in skeletal muscle. The syndrome associated to these mutations (ADOA-1 plus) is complex, consisting of a combination of dominant optic atrophy, progressive external ophtalmoplegia, peripheral neuropathy, ataxia and deafness [57], [58].

As far we know at present no rearrangement but depletion

OPA1, energetic metabolism

Considering the similarity of clinical expression between ADOA-1 and Leber Hereditary Optic Neuropathy (LHON [64]) which is mainly due to mutations in subunits of respiratory complex I, the localization of OPA1 in the IM the major place of oxidative phosphorylation, and its destructuration upon inactivation of the dynamin, it can be postulated that pathogenic OPA1 mutations could lead to energetic defects. Accordingly, RNAi depleted OPA1 cells show a severe reduction of endogenous respiration,

Animal models of ADOA-1

Mitochondrial network abnormalities, bioenergetic failure, increased apoptosis have all been proposed as possible causes of ADOA-1. Recent development of in vivo models of the disease should provide new insights in understanding the physiopathological processes leading to ADOA-1.

Two Opa1 mouse models carrying an in frame deletion of 27 amino acids or a premature stop codon in the GTPase domain have been recently published [42], [67]. Both Opa1 homozygous mouse mutants are lethal at early stage

Conclusion

Numerous data have recently accumulated on the essential role of OPA1 in mitochondria. This dynamin-related protein plays role in mitochondrial fusion, cristae structuration, apoptosis and mtDNA maintenance (Fig. 2), probably reflecting its capacity to modulate IM organization and therefore activities of IM-associated proteins. However there are still gaps in our understanding of the molecular mechanisms underlying these functions. Anti-apoptotic function of OPA1 has been related to its

Acknowledgements

We are indebted to the invaluable support from the following associations: Rétina France, AFM, AMMi, ARC, LNCC and UNADV. EG, AD, TL, AO were recipients of a fellowship from ARC LNCC and FRM.

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Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.
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Optic atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane–associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form, whereas S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca²⁺-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells.
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Citation Excerpt :
DOA presents many analogies with LHON, in terms of target tissue and pattern of RGC loss, however the main clinical difference is that onset is typically before the age of 10 and the natural history is described as a relentless, frequently stable for a long time or slowly progressive optic nerve atrophy, without evidence of spontaneous recovery of vision (Carelli et al., 2004; Yu-Wai-Man et al., 2011). Genetically, over 60% of DOA families are associated with mutations in the OPA1 gene, encoding the major fusogenic protein of inner mitochondrial membrane (Landes et al., 2010; Yu-Wai-Man et al., 2010a; Lenaers et al., 2012). The pathogenic mutations affecting the OPA1 gene can be grossly distinguished in those leading to haploinsufficiency and others, missense mutations, which possibly act through a dominant negative mechanism.
Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively.
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Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity.
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ReviewOPA1 (dys)functions

Abstract

Introduction

Section snippets

OPA1 expression

OPA1, mitochondrial fusion

OPA1, apoptosis

OPA1, mtDNA maintenance

OPA1, energetic metabolism

Animal models of ADOA-1

Conclusion

Acknowledgements

Int J Biochem Cell Biol

FEBS Lett

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Cell

J Biol Chem

Biochim Biophys Acta

FEBS Lett

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

FEBS Lett

Cell

Int J Biochem Cell Biol

Cell

Dev Cell

Mol Cell

Int J Biochem Cell Biol

Biochim Biophys Acta

Exp Neurol

Am J Ophthalmol

Exp Neurol

Mitochondrial dynamics in mammalian health and disease

Physiol Rev

Functions and dysfunctions of mitochondrial dynamics

Nat Rev Mol Cell Biol

Regulation of mitochondrial morphology through proteolytic cleavage of OPA1

EMBO J

Mitochondrial DNA maintenance in yeast requires a protein containing a region related to the GTP-binding domain of dynamin

Genes Dev

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

Nat Genet

The dynamin superfamily: universal membrane tubulation and fission molecules?

Nat Rev Mol Cell Biol

Mutation spectrum and splicing variants in the OPA1 gene

Hum Genet

OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis

Cell Death Differ

OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria

Mol Biol Cell

OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L

J Cell Biol

Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage

J Cell Biol

Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential

Biol Cell

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

Nat Genet

Characterization of OPA1 isoforms isolated from mouse tissues

J Neurochem

The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria

J Cell Biol

Review
OPA1 (dys)functions