The Mitochondrial Pathways of Apoptosis

Abstract

Apoptosis is a process of programmed cell death that serves as a major mechanism for the precise regulation of cell numbers, and as a defense mechanism to remove unwanted and potentially dangerous cells. Studies in nematode, Drosophila and mammals have shown that, although regulation of the cell death machinery is somehow different from one species to another, it is controlled by homologous proteins and involves mitochondria. In mammals, activation of caspases (cysteine proteases that are the main executioners of apoptosis) is under the tight control of the Bcl-2 family proteins, named in reference to the first discovered mammalian cell death regulator. These proteins mainly act by regulating the release of caspases activators from mitochondria. 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 apoptosis. In this chapter, we present the current view on the mitochondrial pathway of apoptosis with a particular attention to new aspects of the regulation of the Bcl-2 proteins family control of mitochondrial membrane permeabilization: the mechanisms implicated in their mitochondrial targeting and activation during apoptosis, the function(s) of the oncosuppressive protein p53 at the mitochondria and the role of the processes of mitochondrial fusion and fission.

TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway

“…Activation of either caspase can cleave PARP and trigger chromosomal DNA fragmentation, which is an apoptotic hallmark. 41 Herein, after confirming the involvement of PI3K/Akt signaling, we then examined the expression of Bad and cytochrome c in TCam-2 cells during CDDP treatment and found they were both positively correlated with TDRG1. Moreover, activation of the caspase cascade was also examined and it could also be regulated by TDRG1.…”

“…32 Cell apoptosis is executed by members of the caspase family, which can be mainly activated by 2 main pathways, including the extrinsic death receptor pathway and the intrinsic mitochondria-related apoptotic pathway. 41 Bad, a pro-apoptotic protein, can be treated as a link between PI3K/Akt signaling and mitochondrial apoptotic pathway. In activation of PI3K/Akt signaling leads to dephosphorylation of Bad and resulting in its translocation from cytoplasm to the mitochondria, which is an important event triggering the release of cytochrome c from mitochondria.…”

La mort cellulaire programmée ne manque pas de vocabulaire

“…Les membres de la famille Bcl-2 régulent la perméabilité mitochondriale, et leur expression et leur activité sont régulées par les divers stress cellulaires, tels que les dommages à l'ADN, le stress métabolique, etc. [4,5]. La voie extrinsèque, quant à elle, implique l'engagement de récepteurs membranaires de mort, les plus courants étant Fas/CD95, TNF receptor 1 (TNFR1) et TRAIL receptor (TRAILR) 1-2 [6].…”

The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death

“…cancers) (1,2). Bak and Bax are pro-apoptotic members of the BCL-2 family that are essential in the initiation of apoptosis (3). During the early steps of apoptosis, Bak undergoes several changes of conformation to induce modifications of mitochondrial permeability associated with the liberation of pro-apoptotic mitochondrial proteins (3).…”

“…Bak and Bax are pro-apoptotic members of the BCL-2 family that are essential in the initiation of apoptosis (3). During the early steps of apoptosis, Bak undergoes several changes of conformation to induce modifications of mitochondrial permeability associated with the liberation of pro-apoptotic mitochondrial proteins (3). Activation of Bak is under the control of several stimuli including the so-called BH3 only proteins, a class of BCl-2 like proteins (3) but also mitochondrial proteins like VDAC2 and Metaxin1 and 2 (4-6) Bak is maintained in an inactive state by its association with the voltage dependent anionic channel type-2 (VDAC2), an isoform of the mitochondrial porins (VDACs) (7,8).…”