1,721,229 research outputs found
Multiple functions of mitochondria-shaping proteins.
No full textMitochondria are complex organelles whose internal structure and cytosolic organization is controlled by a growing number of 'mitochondria-shaping' proteins. These include mitochondrial proteins such as the large dynamin-related GTPases Mitofusin (Mfn) 1 and 2, Optic Atrophy 1 (Opa1); as well as the cytosolic dynamin-related protein 1 (Drp1) and its receptor on the outer mitochondrial membrane Fis1. These proteins influence not only the shape of mitochondria, but also the function of the organelle and eventually integrated cellular signalling cascades, including apoptosis. We undertook a genetic approach to elucidate the function and regulation of these proteins. Opa1 is involved in the regulation of mitochondrial fusion, by co-operating with Mfn1. Moreover, Opa1 independently from mitochondrial fusion regulates the crista remodelling pathway of apoptosis. Oligomers of a membrane bound and a soluble form of Opa1, produced by Parl, an inner membrane rhomboid protease, are disrupted early during apoptosis, leading to remodelling of the mitochondrial cristae and redistribution of the mitochondrial cytochrome c. The importance of this pathway is substantiated by the phenotype of the Parl-/- mouse, which displays excess apoptosis in multiple tissues. Cells lacking Parl are more susceptible to apoptotic stimuli and the reintroduction of a soluble form of Opa1 rescues their phenotype
Proteins that fuse and fragment mitochondria in apoptosis: con-fissing a deadly con-fusion?
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Opening the doors to cytochrome c: changes in mitochondrial shape and apoptosis.
No full textMitochondria are key organelles in the regulation of apoptosis induced by intrinsic stimuli. This is accomplished by the release in the cytoplasm of cytochrome c and of other cofactors that ensure the activation of effector caspases. Multiple changes in the shape of the organelle occur around the time of the release of these factors, including fragmentation of the mitochondrial network and the activation of the so-called "cristae remodeling" pathway. However, contrasting evidence exist on the functional role of these changes. Here we review the molecular mechanisms that control mitochondrial shape, their changes during apoptosis and the role that these changes might play in the amplification of the apoptotic cascade
Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals?
No full textIn certain cell types, apoptosis in response to extracellular stimuli like Fas depends on a mitochondrial amplificatory loop: the apical caspase-8 cleaves and activates the BH3-only member of the Bcl-2 family BID. In turn, BID induces the release of cytochrome c from mitochondria to the cytoplasm, where it is required to fully activate effector caspases. In this issue of The Journal of Cell Biology, Gonzalvez et al. (see p. 681) show that when caspase-8 activation and production of functional BID is required, it is performed on mitochondrial platforms provided by the mitochondrion-specific lipid cardiolipin. Cardiolipin anchors caspase-8 at contact sites between inner and outer mitochondrial membranes, facilitating its self activation. These findings suggests that like other second messengers such as Ca(2+) and cAMP, production of apoptotic messengers can be compartmentalized in close proximity to their intracellular target
D. melanogaster, mitochondria and neurodegeneration: small model organism, big discoveries.
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