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The mitochondrial death pathway: a promising therapeutic target in diseases.

Gupta S, Kass GE, Szegezdi E, Joseph B - J. Cell. Mol. Med. (2009)

Bottom Line: The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP).BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-x(l) and myeloid cell leukaemia 1 prevent MOMP from occurring.The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades.

View Article: PubMed Central - PubMed

Affiliation: NCBES, National University of Ireland, Galway, Ireland. Sanjeev.gupta@nuigalway.ie <Sanjeev.gupta@nuigalway.ie>

ABSTRACT
The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-x(l) and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.

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Related in: MedlinePlus

Schematic representation of the extrinsic and intrinsic apoptotic pathway. In the extrinsic pathway, ligation of receptor to death receptor causes DISC formation leading to caspase-8 activation. In type I cells caspase-8 directly cleaves caspase-3, which starts the death cascade. In type II cells an additional amplification loop is required, which involves tBid-mediated cytochrome c release from mitochondria followed by apoptosome formation. In the intrinsic pathway, stress signals from a variety of insults are sensed by BH3-only pro-apoptotic proteins and communicated to multidomain pro-apoptotic and anti-apoptotic BCL-2 proteins. The functional interplay of the proteins ultimately results in the activation of BAX and BAK at target organelles such as mitochondria and ER, which participate in apoptosis by releasing apoptogenic factors. Cytosolic cytochrome c triggers the formation of apoptosome, followed by activation of caspases-9 and -3. Function of caspase can be modulated on several levels. Activation of caspases at the DISC is inhibited by c-FLIP proteins; activation of effector caspases is inhibited by IAPs (see text for details). Smac/DIABLO and HtrA2/Omi neutralize the inhibition of caspases by IAPs. Smac/DIABLO, HtrA2/Omi, AIF and endo G may also initiate a caspase-independent cell death pathway. Abbreviations: FADD, Fas-associated death domain; DISC, death-inducing signalling complex; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; IAPs; inhibitor of apoptosis proteins; Apaf-1; apoptosis protease activating factor1 and AIF, apoptosis-inducing factor.
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fig01: Schematic representation of the extrinsic and intrinsic apoptotic pathway. In the extrinsic pathway, ligation of receptor to death receptor causes DISC formation leading to caspase-8 activation. In type I cells caspase-8 directly cleaves caspase-3, which starts the death cascade. In type II cells an additional amplification loop is required, which involves tBid-mediated cytochrome c release from mitochondria followed by apoptosome formation. In the intrinsic pathway, stress signals from a variety of insults are sensed by BH3-only pro-apoptotic proteins and communicated to multidomain pro-apoptotic and anti-apoptotic BCL-2 proteins. The functional interplay of the proteins ultimately results in the activation of BAX and BAK at target organelles such as mitochondria and ER, which participate in apoptosis by releasing apoptogenic factors. Cytosolic cytochrome c triggers the formation of apoptosome, followed by activation of caspases-9 and -3. Function of caspase can be modulated on several levels. Activation of caspases at the DISC is inhibited by c-FLIP proteins; activation of effector caspases is inhibited by IAPs (see text for details). Smac/DIABLO and HtrA2/Omi neutralize the inhibition of caspases by IAPs. Smac/DIABLO, HtrA2/Omi, AIF and endo G may also initiate a caspase-independent cell death pathway. Abbreviations: FADD, Fas-associated death domain; DISC, death-inducing signalling complex; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; IAPs; inhibitor of apoptosis proteins; Apaf-1; apoptosis protease activating factor1 and AIF, apoptosis-inducing factor.

Mentions: The mitochondrial ‘intrinsic’ pathway and the death receptor ‘extrinsic’ pathway are the two principal pathways leading to apoptosis, both of which converge on caspase activation (Fig. 1) [1–3]. Caspases are a family of cysteine proteases that, upon activation, cleave specific substrates, leading to the demise of the cell. Based on the order of activation in cell death pathways, caspases are divided into two major groups: initiator caspases and executioner caspases [4]. The subset of caspases that cleave substrates to produce the typical biochemical changes associated with apoptosis are known as executioner caspases, which in mammals are caspases-3, -6 and -7 [5]. Executioner caspases have a short pro-domain and are in turn activated by apical initiator caspases (caspases-2, -8, -9 and -10). Initiator caspases possess long pro-domains that contain one of the two characteristic protein–protein interaction motifs: the death effector domain or the caspase recruitment domain (CARD) and are involved in interacting with the upstream adapter molecules. The initiator caspases are activated by prodomain-mediated dimerization of the zymogens followed by autocatalytic processing [6]. The initiator caspase for the mitochondrial pathway is caspase-9, whereas the initiator caspases for the death receptor pathway are caspases-8 and -10 [7]. Both pathways share the effector caspases (caspases-3, -6 and -7) which cleave cellular substrates leading to apoptotic cell death. Furthermore, caspase-2 is a long prodomain containing initiator caspase involved in stress-induced apoptosis [8]. A protein complex, named PIDDosome has been shown to mediate the activation of caspase-2 in response to genotoxic stimuli [9]. In addition to caspase-2, the PIDDosome contains the p53-induced protein with a death domain (PIDD) and an adapter protein, called RAIDD. Caspase-2 has also been suggested to induce mitochondrial cytochrome c release through a mechanism not yet understood [10, 11]. Caspases-1, -4, -5 and -11 function primarily in the processing of inflammatory cytokines through another proteolytic platform called the inflammosome [12].


The mitochondrial death pathway: a promising therapeutic target in diseases.

Gupta S, Kass GE, Szegezdi E, Joseph B - J. Cell. Mol. Med. (2009)

Schematic representation of the extrinsic and intrinsic apoptotic pathway. In the extrinsic pathway, ligation of receptor to death receptor causes DISC formation leading to caspase-8 activation. In type I cells caspase-8 directly cleaves caspase-3, which starts the death cascade. In type II cells an additional amplification loop is required, which involves tBid-mediated cytochrome c release from mitochondria followed by apoptosome formation. In the intrinsic pathway, stress signals from a variety of insults are sensed by BH3-only pro-apoptotic proteins and communicated to multidomain pro-apoptotic and anti-apoptotic BCL-2 proteins. The functional interplay of the proteins ultimately results in the activation of BAX and BAK at target organelles such as mitochondria and ER, which participate in apoptosis by releasing apoptogenic factors. Cytosolic cytochrome c triggers the formation of apoptosome, followed by activation of caspases-9 and -3. Function of caspase can be modulated on several levels. Activation of caspases at the DISC is inhibited by c-FLIP proteins; activation of effector caspases is inhibited by IAPs (see text for details). Smac/DIABLO and HtrA2/Omi neutralize the inhibition of caspases by IAPs. Smac/DIABLO, HtrA2/Omi, AIF and endo G may also initiate a caspase-independent cell death pathway. Abbreviations: FADD, Fas-associated death domain; DISC, death-inducing signalling complex; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; IAPs; inhibitor of apoptosis proteins; Apaf-1; apoptosis protease activating factor1 and AIF, apoptosis-inducing factor.
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Related In: Results  -  Collection

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fig01: Schematic representation of the extrinsic and intrinsic apoptotic pathway. In the extrinsic pathway, ligation of receptor to death receptor causes DISC formation leading to caspase-8 activation. In type I cells caspase-8 directly cleaves caspase-3, which starts the death cascade. In type II cells an additional amplification loop is required, which involves tBid-mediated cytochrome c release from mitochondria followed by apoptosome formation. In the intrinsic pathway, stress signals from a variety of insults are sensed by BH3-only pro-apoptotic proteins and communicated to multidomain pro-apoptotic and anti-apoptotic BCL-2 proteins. The functional interplay of the proteins ultimately results in the activation of BAX and BAK at target organelles such as mitochondria and ER, which participate in apoptosis by releasing apoptogenic factors. Cytosolic cytochrome c triggers the formation of apoptosome, followed by activation of caspases-9 and -3. Function of caspase can be modulated on several levels. Activation of caspases at the DISC is inhibited by c-FLIP proteins; activation of effector caspases is inhibited by IAPs (see text for details). Smac/DIABLO and HtrA2/Omi neutralize the inhibition of caspases by IAPs. Smac/DIABLO, HtrA2/Omi, AIF and endo G may also initiate a caspase-independent cell death pathway. Abbreviations: FADD, Fas-associated death domain; DISC, death-inducing signalling complex; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; IAPs; inhibitor of apoptosis proteins; Apaf-1; apoptosis protease activating factor1 and AIF, apoptosis-inducing factor.
Mentions: The mitochondrial ‘intrinsic’ pathway and the death receptor ‘extrinsic’ pathway are the two principal pathways leading to apoptosis, both of which converge on caspase activation (Fig. 1) [1–3]. Caspases are a family of cysteine proteases that, upon activation, cleave specific substrates, leading to the demise of the cell. Based on the order of activation in cell death pathways, caspases are divided into two major groups: initiator caspases and executioner caspases [4]. The subset of caspases that cleave substrates to produce the typical biochemical changes associated with apoptosis are known as executioner caspases, which in mammals are caspases-3, -6 and -7 [5]. Executioner caspases have a short pro-domain and are in turn activated by apical initiator caspases (caspases-2, -8, -9 and -10). Initiator caspases possess long pro-domains that contain one of the two characteristic protein–protein interaction motifs: the death effector domain or the caspase recruitment domain (CARD) and are involved in interacting with the upstream adapter molecules. The initiator caspases are activated by prodomain-mediated dimerization of the zymogens followed by autocatalytic processing [6]. The initiator caspase for the mitochondrial pathway is caspase-9, whereas the initiator caspases for the death receptor pathway are caspases-8 and -10 [7]. Both pathways share the effector caspases (caspases-3, -6 and -7) which cleave cellular substrates leading to apoptotic cell death. Furthermore, caspase-2 is a long prodomain containing initiator caspase involved in stress-induced apoptosis [8]. A protein complex, named PIDDosome has been shown to mediate the activation of caspase-2 in response to genotoxic stimuli [9]. In addition to caspase-2, the PIDDosome contains the p53-induced protein with a death domain (PIDD) and an adapter protein, called RAIDD. Caspase-2 has also been suggested to induce mitochondrial cytochrome c release through a mechanism not yet understood [10, 11]. Caspases-1, -4, -5 and -11 function primarily in the processing of inflammatory cytokines through another proteolytic platform called the inflammosome [12].

Bottom Line: The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP).BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-x(l) and myeloid cell leukaemia 1 prevent MOMP from occurring.The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades.

View Article: PubMed Central - PubMed

Affiliation: NCBES, National University of Ireland, Galway, Ireland. Sanjeev.gupta@nuigalway.ie <Sanjeev.gupta@nuigalway.ie>

ABSTRACT
The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-x(l) and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.

Show MeSH
Related in: MedlinePlus