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Journal ArticleDOI

OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion

TL;DR: Evidence is provided that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion.
About: This article is published in Cell.The article was published on 2006-07-14 and is currently open access. It has received 1444 citations till now. The article focuses on the topics: Optic Atrophy 1 & Inner mitochondrial membrane.
Citations
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Journal ArticleDOI
TL;DR: Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria, meaning that mitochondria coordinate the late stage of cellular demise.
Abstract: Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

3,340 citations


Cites background from "OPA1 Controls Apoptotic Cristae Rem..."

  • ...Moreover, recent work suggests that the junctions between ICS and IMS are maintained by Opa1 (optic atrophia 1) (226), an integral protein of the IM with established roles in mitochondrial dynamics (113, 605)....

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  • ...These oligomers may constitute (part of) the structure that preserves the junctions between ICS and IMS in a bottleneck configuration (136, 226)....

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Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4  +183 moreInstitutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

3,301 citations

Journal ArticleDOI
16 Mar 2012-Cell
TL;DR: This work provides a current view of how mitochondrial functions impinge on health and disease and identifies mitochondrial dysfunction as a key factor in a myriad of diseases, including neurodegenerative and metabolic disorders.

2,266 citations


Cites background from "OPA1 Controls Apoptotic Cristae Rem..."

  • ...These junctions are restructured during apoptosis to facilitate release of proapoptotic intermembrane space proteins (Frezza et al., 2006)....

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  • ...This protection is in part due to the role of OPA1 in the integrity of crista junctions and its ability to limit the release of proapoptotic IMS components (Cipolat et al., 2006; Frezza et al., 2006)....

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Journal ArticleDOI
TL;DR: MOMP typically leads to cell death irrespective of caspase activity by causing a progressive decline in mitochondrial function, although cells can survive this under certain circumstances, which may have pathophysiological consequences.
Abstract: Mitochondrial outer membrane permeabilization (MOMP) is often required for activation of the caspase proteases that cause apoptotic cell death. Various intermembrane space (IMS) proteins, such as cytochrome c, promote caspase activation following their mitochondrial release. As a consequence, mitochondrial outer membrane integrity is highly controlled, primarily through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family. Following MOMP by pro-apoptotic BCL-2-associated X protein (BAX) or BCL-2 antagonist or killer (BAK), additional regulatory mechanisms govern the mitochondrial release of IMS proteins and caspase activity. MOMP typically leads to cell death irrespective of caspase activity by causing a progressive decline in mitochondrial function, although cells can survive this under certain circumstances, which may have pathophysiological consequences.

2,219 citations


Cites background from "OPA1 Controls Apoptotic Cristae Rem..."

  • ...Two IMS proteins, optic atrophy protein 1 ( OPA1 ; a dynamin-like GTPase) and presenilins-associated rhomboid-like protein ( PARL ; a rhomboid protease) have been found to regulate cristae remodelling during apoptosi...

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Journal ArticleDOI
04 Dec 2008-Nature
TL;DR: It is shown that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot–Marie–Tooth type IIa, is enriched at the ER–mitochondria interface, and that it tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca2+ uptake.
Abstract: Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.

2,027 citations

References
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Journal ArticleDOI
27 Apr 2001-Science
TL;DR: In this article, the authors found that doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin.
Abstract: Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.

3,942 citations


"OPA1 Controls Apoptotic Cristae Rem..." refers background in this paper

  • ...Expression of wild-type (wt) OPA1 protected mouse embryonic fibroblasts (MEFs) from death induced by apoptotic stimuli that activate the mitochondrial pathway like H2O2, etoposide, staurosporine, and truncated, active BID (tBID) (Wei et al., 2001; Scorrano et al., 2003) (Figures 1A–1D)....

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Journal ArticleDOI
30 Jul 2004-Science
TL;DR: The therapeutic induction of MOMP may restore apoptosis in cancer cells in which it is disabled, and the general rules governing the pathophysiology and controversial issues regarding its regulation are discussed.
Abstract: In the mitochondrial pathway of apoptosis, caspase activation is closely linked to mitochondrial outer membrane permeabilization (MOMP). Numerous pro-apoptotic signal-transducing molecules and pathological stimuli converge on mitochondria to induce MOMP. The local regulation and execution of MOMP involve proteins from the Bcl-2 family, mitochondrial lipids, proteins that regulate bioenergetic metabolite flux, and putative components of the permeability transition pore. MOMP is lethal because it results in the release of caspase-activating molecules and caspase-independent death effectors, metabolic failure in the mitochondria, or both. Drugs designed to suppress excessive MOMP may avoid pathological cell death, and the therapeutic induction of MOMP may restore apoptosis in cancer cells in which it is disabled. The general rules governing the pathophysiology of MOMP and controversial issues regarding its regulation are discussed.

3,258 citations


"OPA1 Controls Apoptotic Cristae Rem..." refers background in this paper

  • ...Cell 126, 177–189, July 14, 2006 ª2006 Elsevier Inc. 185 cytochrome c release and complete the program of mitochondrial dysfunction (Green and Kroemer, 2004)....

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  • ...In a widely accepted model, these proteins can form a channel for the efflux of cytochrome c across the outer mitochondrial membrane (Green and Kroemer, 2004)....

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  • ...Mitochondria amplify apoptosis induced by several stimuli (Green and Kroemer, 2004)....

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  • ...cytochrome c release and complete the program of mitochondrial dysfunction (Green and Kroemer, 2004)....

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Journal ArticleDOI
TL;DR: In the presence of caspase‐3 the amount of active casp enzyme‐8 generated at the DISC determines whether a mitochondria‐independent apoptosis pathway is used (type I cells) or not (type II cells).
Abstract: We have identified two cell types, each using almost exclusively one of two different CD95 (APO‐1/Fas) signaling pathways. In type I cells, caspase‐8 was activated within seconds and caspase‐3 within 30 min of receptor engagement, whereas in type II cells cleavage of both caspases was delayed for ∼60 min. However, both type I and type II cells showed similar kinetics of CD95‐mediated apoptosis and loss of mitochondrial transmembrane potential (ΔΨ m ). Upon CD95 triggering, all mitochondrial apoptogenic activities were blocked by Bcl‐2 or Bcl‐x L overexpression in both cell types. However, in type II but not type I cells, overexpression of Bcl‐2 or Bcl‐x L blocked caspase‐8 and caspase‐3 activation as well as apoptosis. In type I cells, induction of apoptosis was accompanied by activation of large amounts of caspase‐8 by the death‐inducing signaling complex (DISC), whereas in type II cells DISC formation was strongly reduced and activation of caspase‐8 and caspase‐3 occurred following the loss of ΔΨ m . Overexpression of caspase‐3 in the caspase‐3‐negative cell line MCF7‐Fas, normally resistant to CD95‐mediated apoptosis by overexpression of Bcl‐x L , converted these cells into true type I cells in which apoptosis was no longer inhibited by Bcl‐x L . In summary, in the presence of caspase‐3 the amount of active caspase‐8 generated at the DISC determines whether a mitochondria‐independent apoptosis pathway is used (type I cells) or not (type II cells).

3,147 citations


"OPA1 Controls Apoptotic Cristae Rem..." refers background in this paper

  • ...In type I cells, death receptors directly activate effector caspases, bypassing the mitochondrial amplificatory loop (Scaffidi et al., 1998)....

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Journal Article
TL;DR: The complexity of the apoptotic program began to increase with the discovery of Bcl-2, a gene whose product causes resistance to apoptosis in lymphocytes, and the complex role of mitochondria in apoptosis came into focus when biochemical studies identified several mitochondrial proteins that are able to activate cellular apoptotic programs directly.
Abstract: The initial insight into the genetic basis of apoptosis, or programmed cell death, was gained from ingenious studies of the roundworm Caenorhabditis elegans (for review, see Horvitz 1999). These studies revealed a linear pathway whereby the products of two genes, designated Ced-3 andCed-4, were necessary and sufficient to trigger the perfectly timed and orchestrated death of 131 preordained cells during development. The relevance of this pathway to higher animals was established by the discovery of apparent mammalian orthologs of these genes and the demonstration that the mammalian Ced-3-related genes encode proteases (designated caspases) whose activities are responsible for the morphological changes characteristic of apoptosis (for review, see Hengartner 2000). The complexity of the apoptotic program began to increase with the discovery of Bcl-2, a gene whose product causes resistance to apoptosis in lymphocytes (Vaux et al. 1988; McDonnell et al. 1989). Bcl-2 was shown to correct partially the phenotype of a C. elegans mutation in Ced-9, a cell survival gene that functions upstream of Ced-4 and Ced-3 (Vaux et al. 1992). This finding suggested an apparent one-for-one correlation between the C. elegans and mammalian proand antiapoptotic pathways. However, this correlation did not explain two observations made in mammalian cells. First, the Bcl-2 protein was found on the membrane of mitochondria, which were not implicated in C. elegans apoptosis; and second, apoptotic changes could be produced in Xenopus laevis oocyte extracts only when a membrane fraction enriched in mitochondria was present (Hockenberry et al. 1990; Newmeyer et al. 1994). The complex role of mitochondria in mammalian cell apoptosis came into focus when biochemical studies identified several mitochondrial proteins that are able to activate cellular apoptotic programs directly (Liu et al. 1996; Susin et al. 1999; Du et al. 2000; Verhagen et al. 2000; Li et al. 2001). Normally, these proteins reside in the intermembrane space of mitochondria. In response to a variety of apoptotic stimuli, they are released to the cytosol and/or the nucleus. They promote apoptosis either by activating caspases and nucleases or by neutralizing cytosolic inhibitors of this process. A complex picture has emerged in which mitochondrial and cytosolic proapoptotic proteins interact with antiapoptotic proteins with each cell’s life or death hanging in the balance. This review summarizes the recent data on the expanding and complex role of mitochondria in apoptosis.

2,439 citations


"OPA1 Controls Apoptotic Cristae Rem..." refers background in this paper

  • ...They release cytochrome c and other proapoptotic proteins activating a postmitochondrial pathway that culminates in cell demise (Wang, 2001)....

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Journal ArticleDOI
TL;DR: It is concluded that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.
Abstract: Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.

2,239 citations


"OPA1 Controls Apoptotic Cristae Rem..." refers background in this paper

  • ...Mitofusin (MFN) -1 and -2 are dynamin-related proteins of the outer membrane (OM) essential for mitochondrial tethering and fusion (Santel and Fuller, 2001; Legros et al., 2002; Santel et al., 2003; Chen et al., 2003)....

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