Mitochondrial Apoptosis
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Mitochondrial Apoptosis

Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. There are at least two broad pathways that lead to Apoptosis, an "Extrinsic" and an "Intrinsic" Pathway. In both pathways, signaling results in the activation of a family of Cysteine Proteases, named Caspases that act in a proteolytic cascade to dismantle and remove the dying cell. The extrinsic pathway begins outside a cell, when conditions in the extracellular environment determine that a cell must die. The intrinsic apoptosis pathway begins when an injury occurs within the cell. Apoptosis in Mitochondria is the best known intrinsic apoptosis pathway (Ref.1and 2). The Mitochondrial pathway of apoptosis functions in response to various types of intracellular stress including Growth Factor withdrawal, DNA damage, unfolding stresses in the Endoplasmic reticulum and Death Receptor stimulation. Fas a member of the TNFR family typify the classical view of DR (Death Receptor) function and play an important role in stimulating Mitochondrial apoptotic pathway. FasL (Fas Ligand), a homotrimeric protein acts as ligand for Fas and causes oligomerization of its Receptor on binding. The FADD protein binds via its DED (Death Effector Domain) motif to a homologous motif in Procaspase8. The complex of Fas, FADD and Procaspase8 is called the DISC (Death Inducing Signaling Complex). The cofactor function of FADD, in turn, is blocked by interaction with the regulator FLIP (FLICE Inhibitory Protein). Upon recruitment by FADD, Procaspase8 oligomerization drives its activation through self-cleavage. Active Caspase8 then activates downstream Caspases (Caspase3 and Caspase7). In the first pathway Caspase8 cleaves BID (Bcl2 Interacting Protein) and its COOH-terminal part translocates to Mitochondria where it triggers CytoC (Cytochrome-C) release. The released CytoC binds to APAF1 (Apoptotic Protease Activating Factor-1) together with dATP and Procaspase9 and activates Caspase9. Another pathway is that Caspase8 cleaves Procaspase3 directly and activates it. Caspase3 then commits the cell to Apoptosis. Besides DRs, Growth Factors also influence Mitochondrial Apoptosis via PI3K (Phosphatidylinositde-3 Kinase) and Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) pathways. Activation of PI3K pathways leads to Akt activation (Ref. 3, 4, 5 and 6). Following the reception of stress signals, proapoptotic Bcl2 family proteins are activated and subsequently interact with and inactivate antiapoptotic Bcl2 proteins. Proapoptotic members include "Multidomain" BAX family proteins such as BAX, BAK (Bcl2 Antagonist Killer) etc. that display sequence conservation in BH1-3 region and "BH3-only" proteins such as BID, BAD, Noxa, PUMA and BIM (BCL2-Interacting Protein) that have only the short BH3 motif. BAX family proteins act downstream in Mitochondrial disruption, whereas BH3-only proteins act upstream in the pathway, detecting developmental death cures or intracellular damages. The antiapoptotic and proapoptotic protein interaction leads to the destabilization of the Mitochondrial membrane and release of apoptotic factors including CytoC, SMAC (Second Mitochondria-Derived Activator of Caspase), Arts and Omi/HTRA2 (High Temperature Requirement Protein-A2). Bcl2L (Bcl2-Like) and other anti-apoptotic Bcl2 family members reside in the outer Mitochondrial membrane and prevent CytoC release. BAX , BID and BIM are initially inactive and must translocate to Mitochondria to induce apoptosis, either by forming pores in Mitochondria directly or by binding via BH3 domains to Bcl2 and BFL1, and antagonizing these anti-apoptotic proteins. This pore complex may also associate with BAX, BAK1 or BIM, which accelerate channel opening or which causes closure. According to the second mechanism BAX is released from its interaction with 14-3-3 and translocates from cytosol to Mitochondria in response to diverse signals. Here it oligomerizes forming protein pores. Pore formation also takes place in conjunction with the BH3-only Bcl-2 family member BID upon proteolysis to tBID (Truncated BID). BAK1 is located at Mitochondria and has similar pore forming properties to BAX, via its oligomerization and association with tBID. BID is activated by Caspase8-induced cleavage during DR signaling, whereas BIM is released from its association with microtubules (Ref. 5 and 7). Other proteins released from Damaged Mitochondria, SMAC (Second Mitochondria-Derived Activator of Caspase)/ Diablo, Arts and Omi/HTRA2 (High Temperature Requirement Protein-A2), counteract the effect of IAPs (Inhibitor of Apoptosis Proteins), which normally bind and prevent activation of Caspase3. The interaction between Bcl family members, IAPs, SMAC and Omi/HTRA2 is central to the intrinsic Apoptosis pathway. Endoplasmic reticulum stress also takes part in apoptosis by activating Caspase3 via Caspase12. Programmed cell death and its morphologic manifestation of Apoptosis is a conserved pathway that in its basic tenets appears operative in all metazoans. Apoptosis also operates in adult organisms to maintain normal cellular homeostasis. Evidence indicates that insufficient Apoptosis can manifest as Cancer or Autoimmunity, while accelerated cell death is evident in Acute and Chronic Degenerative diseases, Immunodeficiency, and Infertility (Ref. 8 and 9).