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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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Molecular mechanisms of MOMP. (A) According to first model, the pro-apoptotic members of BCL-2 family BAX and BAK form a multimeric pore across the outer mitochondrial membrane upon activation by BH3-only proteins. This channel mediates the release of apoptogenic factors from IMS. (B) According to second model, opening of voltage-gated channel results in mitochondrial matrix swelling and rupture of MOM, releasing IMS proteins in the cytosol. Abbreviations: ANT, adenine nucleotide translocator; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; BH3, BCL-2 homology domain 3; CypD, cyclophilin D; HK, hexokinase; IM, mitochondrial inner membrane; OM, mitochondrial outer membrane and VDAC, voltage-dependent anion channel.
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fig02: Molecular mechanisms of MOMP. (A) According to first model, the pro-apoptotic members of BCL-2 family BAX and BAK form a multimeric pore across the outer mitochondrial membrane upon activation by BH3-only proteins. This channel mediates the release of apoptogenic factors from IMS. (B) According to second model, opening of voltage-gated channel results in mitochondrial matrix swelling and rupture of MOM, releasing IMS proteins in the cytosol. Abbreviations: ANT, adenine nucleotide translocator; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; BH3, BCL-2 homology domain 3; CypD, cyclophilin D; HK, hexokinase; IM, mitochondrial inner membrane; OM, mitochondrial outer membrane and VDAC, voltage-dependent anion channel.

Mentions: During apoptosis in vertebrate cells, the process of MOMP appears to represent a point-of-no-return for many cell types as it appears to commit a cell to death regardless of caspase activity [27]. Why, and how, does MOMP commit a cell to die? MOMP is lethal because it leads to the release of caspase-activating molecules, caspase-independent death effectors and metabolic failure in the mitochondria. Majority of cells appear to be committed to die following MOMP because it leads not only to the activation of the well-established caspase-mediated apoptotic pathway, but, should there be a failure of its execution through insufficient caspase activation, a parallel, caspase-independent cell death pathway is set in motion that is controlled by HtrA2/Omi, AIF and Endo G. However, sympathetic neurons that are induced to undergo apoptosis by withdrawal of nerve growth factors (NGF) can recover upon addition of NGF, even after the release of cytochrome c, provided that caspase activation is blocked [28, 29]. This is due to the fact that neuronal cells express low levels of Apaf-1 and, sufficient levels of endogenous caspase inhibitors such as X-linked IAP (XIAP) to block the ability of cytochrome c to induce apoptosis [30]. The other factors that contribute to cell demise following MOMP are general decline in mitochondrial function. The most important function of mitochondria is the generation of ATP through the process of oxidative phosphorylation. Dissipation of the ΔΨm is a general feature of apoptosis, irrespective of cell type and of the apoptotic stimuli (for a review, see [31]). It has been demonstrated that a reduction in ΔΨm follows within minutes after the release of cytochrome c, but in the absence of caspase activity, mitochondria can regenerate ΔΨm and maintain ATP generation [32]. However, loss of mitochondrial energy production will lead to cell death unless another source of energy is available to the cell. If we are to target the mitochondrial death pathway for disorders connected with apoptosis dysregulation, it will be essential to have a detailed understanding of MOMP and its regulation. The mechanisms of MOMP have been controversial, and there are two principal hypotheses: in the first, MOMP is regulated by the BCL-2 family of proteins, and in the second, by the permeability transition pore (PTP) (Fig. 2) [33].


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

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

Molecular mechanisms of MOMP. (A) According to first model, the pro-apoptotic members of BCL-2 family BAX and BAK form a multimeric pore across the outer mitochondrial membrane upon activation by BH3-only proteins. This channel mediates the release of apoptogenic factors from IMS. (B) According to second model, opening of voltage-gated channel results in mitochondrial matrix swelling and rupture of MOM, releasing IMS proteins in the cytosol. Abbreviations: ANT, adenine nucleotide translocator; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; BH3, BCL-2 homology domain 3; CypD, cyclophilin D; HK, hexokinase; IM, mitochondrial inner membrane; OM, mitochondrial outer membrane and VDAC, voltage-dependent anion channel.
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Related In: Results  -  Collection

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fig02: Molecular mechanisms of MOMP. (A) According to first model, the pro-apoptotic members of BCL-2 family BAX and BAK form a multimeric pore across the outer mitochondrial membrane upon activation by BH3-only proteins. This channel mediates the release of apoptogenic factors from IMS. (B) According to second model, opening of voltage-gated channel results in mitochondrial matrix swelling and rupture of MOM, releasing IMS proteins in the cytosol. Abbreviations: ANT, adenine nucleotide translocator; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2 protein; BH3, BCL-2 homology domain 3; CypD, cyclophilin D; HK, hexokinase; IM, mitochondrial inner membrane; OM, mitochondrial outer membrane and VDAC, voltage-dependent anion channel.
Mentions: During apoptosis in vertebrate cells, the process of MOMP appears to represent a point-of-no-return for many cell types as it appears to commit a cell to death regardless of caspase activity [27]. Why, and how, does MOMP commit a cell to die? MOMP is lethal because it leads to the release of caspase-activating molecules, caspase-independent death effectors and metabolic failure in the mitochondria. Majority of cells appear to be committed to die following MOMP because it leads not only to the activation of the well-established caspase-mediated apoptotic pathway, but, should there be a failure of its execution through insufficient caspase activation, a parallel, caspase-independent cell death pathway is set in motion that is controlled by HtrA2/Omi, AIF and Endo G. However, sympathetic neurons that are induced to undergo apoptosis by withdrawal of nerve growth factors (NGF) can recover upon addition of NGF, even after the release of cytochrome c, provided that caspase activation is blocked [28, 29]. This is due to the fact that neuronal cells express low levels of Apaf-1 and, sufficient levels of endogenous caspase inhibitors such as X-linked IAP (XIAP) to block the ability of cytochrome c to induce apoptosis [30]. The other factors that contribute to cell demise following MOMP are general decline in mitochondrial function. The most important function of mitochondria is the generation of ATP through the process of oxidative phosphorylation. Dissipation of the ΔΨm is a general feature of apoptosis, irrespective of cell type and of the apoptotic stimuli (for a review, see [31]). It has been demonstrated that a reduction in ΔΨm follows within minutes after the release of cytochrome c, but in the absence of caspase activity, mitochondria can regenerate ΔΨm and maintain ATP generation [32]. However, loss of mitochondrial energy production will lead to cell death unless another source of energy is available to the cell. If we are to target the mitochondrial death pathway for disorders connected with apoptosis dysregulation, it will be essential to have a detailed understanding of MOMP and its regulation. The mechanisms of MOMP have been controversial, and there are two principal hypotheses: in the first, MOMP is regulated by the BCL-2 family of proteins, and in the second, by the permeability transition pore (PTP) (Fig. 2) [33].

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