The many shapes of mitochondrial death

Cereghetti, Grazia M.; Scorrano, Luca

doi:10.1038/sj.onc.1209605

Cited by 123 publications

(102 citation statements)

References 82 publications

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“…Mitochondria are central to the physiology of eukaryotic organisms, and the fragmentation and internal ultrastructure changes have been observed in apoptotic cells [6,25]. In the RGV-infected FHM cells, both of mitochondrial size and internal cristae number are reduced.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells

Huang

Gui

et al. 2007

Apoptosis

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A fish cell line, fathead minnow (FHM) cell, was used to investigate the alteration of mitochondrial dynamics and the mechanism of apoptosis under Rana grylio virus (RGV) infection. Microscopy observations, flow-cytometry analysis and molecular marker detection revealed the apoptotic fate of the RGV-infected cells. Some typical apoptotic characteristics, such as chromatin condensation, DNA fragmentation and mitochondrial fragmentation, were observed, and significantly morphological changes of mitochondria, including size, shape, internal structure and distribution, were revealed. The mitochondria in RGV-infected cells were aggregated around the viromatrix, and the aggregation could be blocked by colchicine. Moreover, the Dwm collapse was induced, and caspase-9 and caspase-3 were activated in the RGV-infected cells. In addition, NF-jB activation and intracellular Ca 2+ increase were also detected at different times after infection. The data revealed the detailed dynamics of mitochondrion-mediated apoptosis induced by an iridovirus, and provided the first report on mitochondrial fragmentation during virus-induced apoptosis in fish cells.

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Section: Discussionmentioning

confidence: 99%

“…Mitochondria, which are well-known multifunctional organelles, play prominent roles in supplying energy and regulating apoptosis [2][3][4]. Recently, mitochondrial dynamics and the dramatic alterations, such as mitochondrial fragmentation and crista remodeling, have been reported during the early stages of apoptosis [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells

Huang

Gui

et al. 2007

Apoptosis

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“…In particular, overexpression of Bcl-2 is related to larger mitochondria and larger matrix volumes, which may develop from an increase in crystal folds, resulting in resistance to cytochrome c loss (Kowaltowski et al, 2002). In living cells, mitochondria continuously divide (fission) and fuse (fusion) with one another (Cereghetti and Scorrano, 2006), and Bcl-2 family members are involved in these processes, with the proapoptotic members regulating fission, and the antiapoptotic members regulating fusion of mitochondria (Delivani et al, 2006). We show herein the ability of the bacterial toxin CNF1 to induce a modification of the mitochondrial network mainly consisting in the appearance of elongated and interconnected mitochondria that spread throughout the cell body.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by some pathogenic strains of Escherichia coli that specifically activates Rho, Rac, and Cdc42 GTPases. We previously reported that this toxin prevents the ultraviolet-Binduced apoptosis in epithelial cells, with a mechanism that remained to be defined. In this work, we show that the proteasomal degradation of the Rho GTPase is necessary to achieve cell death protection, because inhibition of Rho degradation abolishes the prosurvival activity of CNF1. We hypothesize that Rho inactivation allows the activity of Rac to become dominant. This in turn leads to stimulation of the phosphoinositide 3-kinase/Akt/I B kinase/nuclear factor-B prosurvival pathway and to a remarkable modification in the architecture of the mitochondrial network, mainly consisting in the appearance of elongated and interconnected mitochondria. Importantly, we found that Bcl-2 silencing reduces the ability of CNF1 to protect cells against apoptosis and that it also prevents the CNF1-induced mitochondrial changes. It is worth noting that the ability of a bacterial toxin to induce such a remodeling of the mitochondrial network is herein reported for the first time. The possible pathophysiological relevance of this finding is discussed. INTRODUCTIONToday, it is largely acknowledged that apoptosis, besides being an evolutionary conserved form of cell death that plays a pivotal role during development, morphogenesis, and cell homeostasis, is also critically implied in a constantly growing number of diseases (Fadeel and Orrenius, 2005). In fact, apoptosis can be regarded as a widespread strategy exploited by pathogenic bacteria to favor their own survival or spreading in the host , often by producing protein toxins that mediate their long-range cross-talk with host cells. In this context, we have previously reported the ability of a protein toxin from Escherichia coli, namely the cytotoxic necrotizing factor 1 (CNF1), to prevent the ultraviolet-B (UVB)-induced apoptosis and to increase the expression of antiapoptotic Bcl-2 family proteins (Fiorentini et al., 1998). The precise mechanism by which CNF1 allows cells to survive, however, is not yet defined.CNF1 is a protein toxin produced by some pathogenic strains of E. coli mainly involved in extraintestinal infections (Landraud et al., 2000). In eukaryotic cells, CNF1 binds to its receptor, reported to be the receptor of laminin , and it is endocytosed and released into the cytoplasm by an acidic-dependent mechanism (Contamin et al., 2000). Once in the cytoplasm, CNF1 exerts its enzymatic activity that is represented by deamidation of a pivotal glutamine residue of the guanosine triphosphate (GTP)-binding proteins Rho, Rac, and Cdc42 (glutamine 63 of Rho or glutamine 61 of Rac and Cdc42), giving rise to a glutamic acid (Flatau et al., 1997;Schmidt et al., 1997;Lerm et al., 1999). The glutamine residue modified by CNF1 lies in the switch 2 domain of Rho proteins, which is involved in GTP hydrolysis; thus, the modification exerted by CNF1...

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“…In certain cell types mitochondria are organized in networks of interconnected organelles. 7 Ultrastructurally, the IM can be further subdivided in an inner boundary membrane and in the cristae compartment, bag-like folds of the IM connected to it via narrow tubular junctions. 9 The ultrastructure and the reticular organization of the organelle is determined by mitochondria-shaping proteins that impinge on the equilibrium between fusion and fission processes.…”

Section: Regulation Of Mitochondrial Shapementioning

confidence: 99%

“…In the recent years this assumption has been subverted by two observations: mitochondrial network undergoes fragmentation and topology of the IM is altered in concurrence with the functional and proteomic changes occurring to the apoptotic mitochondrion. 7 These observations prompted several groups to investigate the mechanisms regulating mitochondrial morphology in healthy and dying cells and a new, unexpected player came into the game: a rhomboid protease of the inner mitochondrial membrane (IMM) called presenilin-associated rhomboid-like (Parl), originally identified in a yeast two-hybrid screen as an interactor of presenilin, 8 a protein involved in processing of the amyloid b-peptide. Here, we review the recent progresses in the regulation of mitochondrial shape during cell life and death, focusing on the role of this mitochondrial rhomboid protease.…”

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confidence: 99%

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

Scorrano

2007

Cell Death Differ

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132

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Mitochondria are crucial amplifiers of death signals. They release cytochrome c and other pro-apoptotic factors required to fully activate effector caspases. This release is accompanied by fragmentation of the mitochondrial reticulum and by remodelling of the internal structure of the organelle. Here we review data supporting the existence of a regulatory network in the inner mitochondrial membrane that includes optic atrophy 1 (Opa1), a dynamin-related protein, and presenilin-associated rhomboidlike (Parl), a rhomboid protease. Opa1 regulates remodelling of the cristae independent of its effect on fusion. Cristae remodelling conversely requires Parl, which participates in the production of a soluble form of Opa1 retrieved together with the integral membrane one in oligomers that are disrupted early during apoptosis. Parl itself is regulated by proteolysis to generate a cleaved form, which in turn modulates the shape of the mitochondrial reticulum. Cleavage of Parl depends on its phosphorylation state around the cleavage site, implicating mitochondrial kinases and phosphatases in the regulation of mitochondrial shape.

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The many shapes of mitochondrial death

Cited by 123 publications

References 82 publications

Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells

Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

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