Mitochondria and cancer: is there a morphological connection?

Alirol, Emilie; Martinou, Jean‐Claude

doi:10.1038/sj.onc.1209600

Cited by 156 publications

(113 citation statements)

References 133 publications

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“…The pathogenesis of CNF1-producing E. coli can also be reinforced by the toxininduced release of proinflammatory cytokines from epithelial or endothelial (Munro et al, 2004) cells, thus causing an inflammatory reaction that, once chronically established, can potentially be implicated in transformation of infected tissues. Finally, because the mi- tochondrial remodeling is of direct relevance for the role of these organelles in cell physiology and the mitochondrial dysfunction can contribute to a number of human disorders, including cancer (Alirol and Martinou, 2006), the role of CNF1 as a factor favoring transformation is further supported by the herein reported novel findings.…”

Section: Discussionsupporting

confidence: 70%

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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Section: Discussionsupporting

confidence: 70%

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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“…It is often activated during normal development and in response to diverse stimuli [1]. 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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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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“…MOMP is an extremely complex phenomenon that is regulated by proteins from the Bcl-2 family (Cheng et al, 2006), proteins contained in the permeability transition pore complex (Brenner and Grimm, 2006), proteins that affect mitochondrial dynamics (fusion and fission) (Alirol and Martinou, 2006;Cereghetti and Scorrano, 2006) and even transcription factors (such as the tumor-suppressor protein p53) that can translocate from the nucleus to mitochondria to stimulate MOMP (Moll et al, 2006). MOMP inhibition resulting in disabled apoptosis is important for the development of solid tumors.…”

Section: Mitochondria In Cancermentioning

confidence: 99%