Mitochondria and apoptosis

Abstract

Programmed cell death serves as a major mechanism for the precise regulation of cell numbers and as a defense mechanism to remove unwanted and potentially dangerous cells. Despite the striking heterogeneity of cell death induction pathways, the execution of the death program is often associated with characteristic morphological and biochemical changes, and this form of programmed cell death has been termed apoptosis.Genetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential for cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activation of the death program. Caspases (cysteine aspartases) are the mammalian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the first discovered mammalian cell death regulator. In both worm and mammalian cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processing into active killers.Two main mechanisms of action have been proposed to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2s would maintain cell survival by dragging caspases to intracellular membranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosis protease-activating factor 1) could be the mammalian equivalent of CED-4 and could be the physical link between Bcl-2s and caspases. In the second one, Bcl-2 would act by regulating the release from mitochondria of some caspases activators: cytochrome c and/or AIF (apoptosis-inducing factor). This crucial position of mitochondria in programmed cell death control is reinforced by the observation that mitochondria contribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, we examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the maintenance of the symbiosis between the bacterial ancestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival.

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

“…As such, it is conceivable that perforin induces death through perturbation of mitochondrial stability. Mitochondrial membrane damage can cause the release of cytochrome c, a molecule involved in respiration [31,32]. Once in the cytosol, it forms an apoptosome with Apaf1 and procaspase 9, resulting in activation of caspase 9.…”

“…Once in the cytosol, it forms an apoptosome with Apaf1 and procaspase 9, resulting in activation of caspase 9. Caspase 9 is another activator of caspase 3 (reviewed in [32]). However, caspase 9 processing was not detected in lysates of apoptotic cells, despite the presence of active, processed caspase 3.…”

The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation

“…The extrinsic pathway is triggered by a receptor/ligand interaction mechanism which involves the recruitment of the proximal regulatory caspase-8 to the death receptor complex, resulting in cleavage of the effector caspases-3 and -7, whereas the intrinsic pathway is associated with the release of cytochrome c from mitochondria and the subsequent activation of Apaf-1, causing multimerization and autocleavage of caspase-9 and the further cleavage of the effector caspases [29,32,37,41,45]. A third pathway of apoptosis may exist, mediated by endoplasmic reticulum (ER) stress and characterized by cleavage of caspase-12 [31,36], further indicating the complex nature of the regulatory pathways of apoptosis.…”

Intracellular K+ inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release

“…A number of apoptosis-related proteins, including AIF, cytochrome c and Smac/Diablo, are stored in the mitochondria and released only upon the requisite apoptotic signal. [5][6][7] Furthermore, phosphorylation of Bad and procaspase-9 by Akt and nitrosylation of procaspase-3 at its catalytic cysteine residue promotes cell survival. [8][9][10] Similarly, heat shock protein 70 binds to Apaf-1 and prevents the formation of the apoptosome.…”