Apoptosis and survival - Regulation of Apoptosis by Mitochondrial Proteins

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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:

  1. Khosravi-Far R, Esposti MD
    Death receptor signals to mitochondria. Cancer biology & therapy 2004 Nov;3(11):1051-7
  2. Shakibaei M, Schulze-Tanzil G, Takada Y, Aggarwal BB
    Redox regulation of apoptosis by members of the TNF superfamily. Antioxidants & redox signaling 2005 Mar-Apr;7(3-4):482-96
  3. Cohen GM
    Caspases: the executioners of apoptosis. The Biochemical journal 1997 Aug 15;326 ( Pt 1):1-16
  4. Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, Yonehara S
    The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis. Nature 1999 Apr 29;398(6730):777-85
  5. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH
    Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell death and differentiation 2000 Dec;7(12):1166-73
  6. Gong XM, Choi J, Franzin CM, Zhai D, Reed JC, Marassi FM
    Conformation of membrane-associated proapoptotic tBid. The Journal of biological chemistry 2004 Jul 9;279(28):28954-60
  7. Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ
    Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. The Journal of cell biology 2001 Jun 11;153(6):1265-76
  8. Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E, Saikumar P
    Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release. The Journal of biological chemistry 2003 Feb 14;278(7):5367-76
  9. Grinberg M, Sarig R, Zaltsman Y, Frumkin D, Grammatikakis N, Reuveny E, Gross A
    tBID Homooligomerizes in the mitochondrial membrane to induce apoptosis. The Journal of biological chemistry 2002 Apr 5;277(14):12237-45
  10. Saito M, Korsmeyer SJ, Schlesinger PH
    BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nature cell biology 2000 Aug;2(8):553-5
  11. Guo F, Nimmanapalli R, Paranawithana S, Wittman S, Griffin D, Bali P, O'Bryan E, Fumero C, Wang HG, Bhalla K
    Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 2002 May 1;99(9):3419-26
  12. Halestrap A
    Biochemistry: a pore way to die. Nature 2005 Mar 31;434(7033):578-9
  13. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X
    Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997 Nov 14;91(4):479-89
  14. Yan W, Samson M, Jegou B, Toppari J
    Bcl-w forms complexes with Bax and Bak, and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. Molecular endocrinology (Baltimore, Md.) 2000 May;14(5):682-99
  15. Ke N, Godzik A, Reed JC
    Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. The Journal of biological chemistry 2001 Apr 20;276(16):12481-4
  16. Shangary S, Johnson DE
    Peptides derived from BH3 domains of Bcl-2 family members: a comparative analysis of inhibition of Bcl-2, Bcl-x(L) and Bax oligomerization, induction of cytochrome c release, and activation of cell death. Biochemistry 2002 Jul 30;41(30):9485-95
  17. Ruffolo SC, Shore GC
    BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. The Journal of biological chemistry 2003 Jul 4;278(27):25039-45
  18. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC
    Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 2003 May 22;423(6938):456-61
  19. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC
    Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular cell 2005 Feb 4;17(3):393-403
  20. Cregan SP, Dawson VL, Slack RS
    Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004 Apr 12;23(16):2785-96

  1. Khosravi-Far R, Esposti MD
    Death receptor signals to mitochondria. Cancer biology & therapy 2004 Nov;3(11):1051-7
  2. Shakibaei M, Schulze-Tanzil G, Takada Y, Aggarwal BB
    Redox regulation of apoptosis by members of the TNF superfamily. Antioxidants & redox signaling 2005 Mar-Apr;7(3-4):482-96
  3. Cohen GM
    Caspases: the executioners of apoptosis. The Biochemical journal 1997 Aug 15;326 ( Pt 1):1-16
  4. Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, Yonehara S
    The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis. Nature 1999 Apr 29;398(6730):777-85
  5. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH
    Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell death and differentiation 2000 Dec;7(12):1166-73
  6. Gong XM, Choi J, Franzin CM, Zhai D, Reed JC, Marassi FM
    Conformation of membrane-associated proapoptotic tBid. The Journal of biological chemistry 2004 Jul 9;279(28):28954-60
  7. Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ
    Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. The Journal of cell biology 2001 Jun 11;153(6):1265-76
  8. Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E, Saikumar P
    Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release. The Journal of biological chemistry 2003 Feb 14;278(7):5367-76
  9. Grinberg M, Sarig R, Zaltsman Y, Frumkin D, Grammatikakis N, Reuveny E, Gross A
    tBID Homooligomerizes in the mitochondrial membrane to induce apoptosis. The Journal of biological chemistry 2002 Apr 5;277(14):12237-45
  10. Saito M, Korsmeyer SJ, Schlesinger PH
    BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nature cell biology 2000 Aug;2(8):553-5
  11. Guo F, Nimmanapalli R, Paranawithana S, Wittman S, Griffin D, Bali P, O'Bryan E, Fumero C, Wang HG, Bhalla K
    Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 2002 May 1;99(9):3419-26
  12. Halestrap A
    Biochemistry: a pore way to die. Nature 2005 Mar 31;434(7033):578-9
  13. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X
    Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997 Nov 14;91(4):479-89
  14. Yan W, Samson M, Jegou B, Toppari J
    Bcl-w forms complexes with Bax and Bak, and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. Molecular endocrinology (Baltimore, Md.) 2000 May;14(5):682-99
  15. Ke N, Godzik A, Reed JC
    Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. The Journal of biological chemistry 2001 Apr 20;276(16):12481-4
  16. Shangary S, Johnson DE
    Peptides derived from BH3 domains of Bcl-2 family members: a comparative analysis of inhibition of Bcl-2, Bcl-x(L) and Bax oligomerization, induction of cytochrome c release, and activation of cell death. Biochemistry 2002 Jul 30;41(30):9485-95
  17. Ruffolo SC, Shore GC
    BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. The Journal of biological chemistry 2003 Jul 4;278(27):25039-45
  18. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC
    Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 2003 May 22;423(6938):456-61
  19. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC
    Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular cell 2005 Feb 4;17(3):393-403
  20. Cregan SP, Dawson VL, Slack RS
    Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004 Apr 12;23(16):2785-96

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