OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion

Frezza, Christian; Cipolat, Sara; Brito, Olga Martins de; Micaroni, Massimo; Beznoussenko, Galina V.; Rudka, Tomasz; Bartoli, Davide; Polishuck, Roman; Danial, Nika N.; Strooper, Bart De; Scorrano, Luca

doi:10.1016/j.cell.2006.06.025

Cited by 1,456 publications

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“…Two recent studies by Scorrano and de Strooper group have shed light on the possible mechanism of cristae remodeling during cell death through the fusion protein Opa1 [96,131]. Opa1 is processed from the long membrane anchored form of Opa1 (l-Opa1) to a soluble short form (s-Opa1).…”

Section: Mitochondrial Cristae Structure and Cell Death: Demolition Fmentioning

confidence: 99%

Mitochondrial dynamics in the regulation of neuronal cell death

2007

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Mitochondria undergo continuous fission and fusion events in physiological situations. Fragmentation of mitochondria during cell death has been shown to play a key role in cell death progression, including release of the mitochondrial apoptotic proteins. Ultrastructural changes in mitochondria, such as cristae remodeling, is also involved in cell death initiation. Here, we emphasize the important role of mitochondrial fission/fusion machinery in neuronal cell death. Unlike many other cell types such as immortalized cell lines, neurons are distinct morphologically and functionally. We will discuss how this uniqueness presents special challenges in the cellular response to neurotoxic stresses, and how this affects the mitochondrial dynamics in the regulation of cell death in neurons.

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Section: Mitochondrial Cristae Structure and Cell Death: Demolition Fmentioning

confidence: 99%

Mitochondrial dynamics in the regulation of neuronal cell death

2007

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“…This protocol describes how to obtain functional, purified, intact mitochondria from three different sources: liver 16 , skeletal muscle 17 and cultured cells 18 . These variants intend to be exemplificative and not exhaustive, as they do not cover the different sources from which mitochondria can be isolated.…”

Section: Introductionmentioning

confidence: 99%

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

2007

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“…We and others have shown that OPA1 is a good candidate for the regulation of the cristae structure in the mitochondria. 11,14 Indeed, downregulation of OPA1 affect the IMM structure and integrity, leading to respiration defects and DC m loss, fission of the mitochondrial network, impairment of growth and apoptosis 11,[14][15][16][17][18] and OPA1 overexpression protects from cyt c mobilization by tightening cristae junctions. 14 OPA1 is also partially associated to the OMM, on its IMS side, where it might interact with Mfn1 to promote fusion of the mitochondrial network, or maintain a physical link between the OMM and IMM.…”

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

et al. 2006

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In most eucaryote cells, release of apoptotic proteins from mitochondria involves fission of the mitochondrial network and drastic remodelling of the cristae structures. The intramitochondrial dynamin OPA1, as a potential central actor of these processes, exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b, which functions remain undetermined. Here, we show that Ex4 that is conserved throughout evolution confers functions to OPA1 involved in the maintenance of the DW m and in the fusion of the mitochondrial network. Conversely, Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates. The drastic changes of OPA1 variant abundance in different organs suggest that nuclear splicing can control mitochondrial dynamic fate and susceptibility to apoptosis and pathologies. Mitochondrial membrane dynamics, involving both the fusionfission of the mitochondrial network and remodelling of cristae structures, are essential processes in cellular adaptation to changes of growth condition and programmed cell death. [1][2][3] The outer and inner mitochondrial membrane (OMM and IMM) dynamics crosstalk and involve large GTPases: respectively, the mitofusins Mfn1 and Mfn2 4,5 and the dynamin-related DRP1 6 on the OMM, and the dynaminrelated OPA1, localized in the inter membrane space (IMS). 7 Mitochondrial fission is tightly associated to the apoptotic process, and physical and functional interactions between apoptotic proteins including Bcl2-homologue domains and DRP1 and mitofusins have been identified. 8 In addition, BH3-only proapoptotic proteins, exemplified by tBid and Bik, might act directly on the IMM structure, although their intramitochondrial target remains unknown. 3,9 Further crosstalk between the OMM and the IMM is exemplified by the OMM fission and fusion regulation by the mitochondrial membrane potential (DC m ) 10 and structural integrity 11 and by interaction between OPA1 and Mfn1. 12 The IMM forms, an architecturally complex structure, that has been reconsidered recently in the light of tomography analysis associated to transmission electron microscopy (TEM). Indeed, tubular inner membrane junctions, called cristae junctions, have been evidenced between the IMM facing the OMM and the vesicular-shaped cristae. 13 In vertebrate cells, during the apoptotic process, the cristae junction topology is drastically modified to mobilize cytochrome c (cyt c) from the intracristae compartment to the IMS, before its extensive release in the cytoplasm. 3,9 How this process is physically controlled and related to the OMM dynamic remains unknown. We and others have shown that OPA1 is a good candidate for the regulation of the cristae structure in the mitochondria. 11,14 Indeed, downregulation of OPA1 affect the IMM structure and integrity, leading to respiration defects and DC m loss, fission of the mitochondrial network, impairment of growth and apoptosis 11,14-18 and OPA1 overexpressio...

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OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion

Cited by 1,456 publications

References 57 publications

Mitochondrial dynamics in the regulation of neuronal cell death

Mitochondrial dynamics in the regulation of neuronal cell death

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

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

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