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CED-9 and EGL-1: A Duo Also Regulating Mitochondrial Network Morphology

Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
Molecular Cell (Impact Factor: 14.46). 04/2006; 21(6):730-2. DOI: 10.1016/j.molcel.2006.03.003
Source: PubMed

ABSTRACT In both Caenorhabditis elegans and mammals, Bcl-2 family members control apoptosis. In this issue of Molecular Cell, a paper by Delivani et al. (2006) sheds light on a new role of Bcl-2 family members as regulators of mitochondrial network morphology.

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    • "In summary, although Bcl-2 family members have been shown to be involved in apoptosis and CED-9 is localized to the mitochondrial membrane, it is not known whether it is associated with MOMP (Estaquier and Arnoult 2006). In the fruit fly Drosophila, the involvement of mitochondria in cell death is less clear and they probably do not undergo MOMP (Varkey et al. 1999), although recent research findings may overturn this notion (see below; Challa et al. 2007; Igaki et al. 2007). "
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    ABSTRACT: Caspase proteases are key mediators of apoptotic cell death, playing both regulatory and executioner roles. Traditionally, the requirement for caspase activity has been one of the defining features of classical apoptosis and has been used to discriminate between different types of cell death. However, it is becoming increasingly apparent that a wide spectrum of cell death paradigms does not involve caspase proteases. It is now established that mostly in cases of pathological and accidental cell death and also in certain situations of developmentally programmed cell death, cellular destruction proceeds without activation of caspases. Instead, alternative, caspase-independent mechanisms are brought to bear. In this chapter, we survey caspase-independent cell death mechanisms in two invertebrate animal models, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. We highlight common elements among different instances of cell demise, which point to evolutionarily conserved death mechanisms. Such mechanisms are likely to be relevant to pathological cell death in humans also.
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    • "This observation raises the possibility that these diseases may be caused by inappropriate and premature cell death. Indeed, recent evidence suggests that the cellular housekeeping role of antiapoptotic Bcl2 family members is to regulate mitochondrial dynamics (Estaquier and Arnoult, 2006). Another possible common cellular defect caused by deficient mitochondrial fusion in humans is the loss of membrane potential and mtDNA, which encodes essential components of respiratory-chain complexes. "
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    ABSTRACT: Mitochondrial outer- and inner-membrane fusion events are coupled in vivo but separable and mechanistically distinct in vitro, indicating that separate fusion machines exist in each membrane. Outer-membrane fusion requires trans interactions of the dynamin-related GTPase Fzo1, GTP hydrolysis, and an intact inner-membrane proton gradient. Inner-membrane fusion also requires GTP hydrolysis but distinctly requires an inner-membrane electrical potential. The protein machinery responsible for inner-membrane fusion is unknown. Here, we show that the conserved intermembrane-space dynamin-related GTPase Mgm1 is required to tether and fuse mitochondrial inner membranes. We observe an additional role of Mgm1 in inner-membrane dynamics, specifically in the maintenance of crista structures. We present evidence that trans Mgm1 interactions on opposing inner membranes function similarly to tether and fuse inner membranes as well as maintain crista structures and propose a model for how the mitochondrial dynamins function to facilitate fusion.
    Cell 11/2006; 127(2):383-95. DOI:10.1016/j.cell.2006.09.021 · 33.12 Impact Factor
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    ABSTRACT: Mitochondria are the product of an ancient endosymbiotic event between an alpha-proteobacterium and an archael host. An early barrier to overcome in this relationship was the control of the bacterium's proliferation within the host. Undoubtedly, the bacterium (or protomitochondrion) would have used its own cell division apparatus to divide at first and, today a remnant of this system remains in some "ancient" and diverse eukaryotes such as algae and amoebae, the most conserved and widespread of all bacterial division proteins, FtsZ. In many of the eukaryotes that still use FtsZ to constrict the mitochondria from the inside, the mitochondria still resemble bacteria in shape and size. Eukaryotes, however, have a mitochondrial morphology that is often highly fluid, and in their tubular networks of mitochondria, division is clearly complemented by mitochondrial fusion. FtsZ is no longer used by these complex eukaryotes, and may have been replaced by other proteins better suited to sustaining complex mitochondrial networks. Although proteins that divide mitochondria from the inside are just beginning to be characterized in higher eukaryotes, many division proteins are known to act on the outside of the organelle. The most widespread of these are the dynamin-like proteins, which appear to have been recruited very early in the evolution of mitochondria. The essential nature of mitochondria dictates that their loss is intolerable to human cells, and that mutations disrupting mitochondrial division are more likely to be fatal than result in disease. To date, only one disease (Charcot-Marie-Tooth disease 2A) has been mapped to a gene that is required for mitochondrial division, whereas two other diseases can be attributed to mutations in mitochondrial fusion genes. Apart from playing a role in regulating the morphology, which might be important for efficient ATP production, research has indicated that the mitochondrial division and fusion proteins can also be important during apoptosis; mitochondrial fragmentation is an early triggering (and under many stimuli, essential) step in the pathway to cell suicide.
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