Apoptosis and survival - Regulation of Apoptosis by Mitochondrial Proteins

Regulation of Apoptosis by Mitochondrial Proteins

Apoptosis is an evolutionarily conserved type of programmed cell death essential for development, homeostasis, and self-defense against infection. It can be triggered by a number of factors including UV- or gamma-irradiation, chemotherapeutic drugs, or signaling by death receptors. There are two major pathways in mammals that are involved in the initiation of apoptosis. These are the 'extrinsic' death receptor pathway, and the 'intrinsic' mitochondrial pathway. These pathways can act independently to initiate the death machinery, however there is delicate coordination and cross talk between these pathways that leads to the activation of the caspase cascade [1], [2].

Activation of the death domain receptors, such as Tumor necrosis factor receptor superfamily member 1A (TNF-R1) and Fas TNF receptor superfamily member 6 (FasR(CD95)) leads to the cleavage and activation of the pro-Caspase-8 [3], [4]. Caspase-8 cleaves BH3 interacting domain death agonist (Bid). Following cleavage, the carboxyl-terminal fragment (tBid) of Bid transmits the apoptotic signal from the death receptors to the mitochondria. tBid targets the mitochondria and induces oligomerization of BCL2-associated X protein (Bax) and BCL2-antagonist/killer 1 (Bak) in the cellular outer membrane [5], [6]. However, oligomerization of both Bax and Bak may occur independently of the cleavage of Bid and/or translocation of Bid from cytosol to mitochondria [7], [8]. tBid also forms oligomers in the mitochondrial membrane [9]. The Bcl-2 family members may function as pore-forming proteins (Bak-, Bax- and Bid-pores) [5], [10].

Cytochrome-c and the second mitochondria-derived activator of caspases Smac/Diablo are released into cytosol and pass through the Bak-, Bax- and Bid-pores. This leads to rupture of the outer membrane [11], [12]. Once released from mitochondria, Cytochrome-c binds to and activates Apoptotic peptidase activating factor 1 (Apaf-1). Activated Apaf-1 then forms complexes with pro-Caspase 9. This results in the activation of caspase cascade and induction of apoptosis [13].

Anti-apoptotic proteins B-cell CLL/lymphoma 2 (Bcl-2), BCL2-like 1 (Bcl-XL), BCL2-like 2 (Bcl-W), BCL2-like 10 (Bcl-B), BCL2-related protein A1 (BFL1), and Myeloid cell leukemia sequence 1 (Mcl-1) suppress apoptosis induced by either Bax or Bak. These anti-apoptotic proteins selectively bind to Bax and Bak, block their oligomerization and induce closing pores [14], [15], [16], [17].

Mitochondrially encoded 16S RNA (Humanin) is another anti-apoptotic peptide that was identified recently. It prevents the translocation of Bax from cytosol to mitochondria, blocks Bax association and suppresses Cytochrome c release from mitochondria into cytosol [18].

The BH3-only proteins (Bid, Harakiri BCL2 interacting protein (HRK), Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), Modulator of apoptosis 1 (MAP1), BCL2-like 11 (BIM), Bcl2 modifying factor (BMF), BCL2-interacting killer (BIK), BCL2-associated agonist of cell death (BAD), and BCL2 binding component 3 (Puma)) monitor cellular well being. Different damage signals trigger their binding to anti-apoptotic proteins, thereby initiating cell death. Some BH3-only proteins exhibit binding to all the anti-apoptotic proteins, while others exhibit marked selectivity. This selectivity accounts for differences in the proapoptotic activity of the BH3-only proteins and apoptosis relies on selective interactions between particular subsets of these proteins [19].

Mitochondria can also release factors involved in caspase-independent cell death including Apoptosis-inducing factor, mitochondrion-associated 1 (Aif). This protein translocates to the nucleus and induces DNA fragmentation in a caspase-independent manner [20].

References:

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