Mitochondria and the Bcl-2 family proteins in apoptosis signaling pathways

Two main intracellular apoptosis cascades, the receptor and the mitochondria pathway, have been identified. The mitochondrial pathway is controlled by the Bcl-2 proteins. This protein family contains members with either pro- or anti-apoptotic activity. When activated the pro-apoptotic multidomain proteins permeabilized the outer mitochondrial membrane, resulting in the release of proteins from the intermembrane space. Several proteins, including cytochrome c, Smac/DIABLO, HtrA2/Omi, endonuclease G and AIF, normally sequestered in the mitochondria induce or promote apoptosis once released into the cytosol. Although, apoptosis is an essential physiological process in multicellular organisms it is also involved in a wide range of pathological conditions.

[1]  M. Fujimura,et al.  Cytosolic Redistribution of Cytochrome C after Transient Focal Cerebral Ischemia in Rats , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  W. Brück,et al.  Association of Increased Bcl‐2 Expression with Rescue from Tumor Necrosis Factor‐α‐Induced Cell Death in the Oligodendrocyte Cell Line OLN‐93 , 2000, Journal of neurochemistry.

[3]  K. Maehara,et al.  Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction. , 2000, Cardiovascular research.

[4]  R. Meadows,et al.  X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death , 1996, Nature.

[5]  D. Newmeyer,et al.  Cell-free apoptosis in Xenopus egg extracts: Inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria , 1994, Cell.

[6]  B. Corfe,et al.  Cell Damage-induced Conformational Changes of the Pro-Apoptotic Protein Bak In Vivo Precede the Onset of Apoptosis , 1999, The Journal of cell biology.

[7]  D. Green,et al.  Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD‐specific caspase activation and independently of mitochondrial transmembrane depolarization , 1998, The EMBO journal.

[8]  Y. Hsu,et al.  Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Jacob,et al.  Apoptosis and related proteins in different stages of human atherosclerotic plaques. , 1998, Circulation.

[10]  M. Venkatachalam,et al.  Bcl-2 Prevents Bax Oligomerization in the Mitochondrial Outer Membrane* , 2001, The Journal of Biological Chemistry.

[11]  Jean-Claude Martinou,et al.  Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia , 1994, Neuron.

[12]  J. Beckmann,et al.  Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. , 1998, Immunity.

[13]  Ruedi Aebersold,et al.  Molecular characterization of mitochondrial apoptosis-inducing factor , 1999, Nature.

[14]  P. Krammer,et al.  Regulation of death receptor-mediated apoptosis pathways. , 2000, The international journal of biochemistry & cell biology.

[15]  E. White,et al.  E1B 19K Blocks Bax Oligomerization and Tumor Necrosis Factor Alpha-Mediated Apoptosis , 2001, Journal of Virology.

[16]  S. Korsmeyer,et al.  BAX-dependent transport of cytochrome c reconstituted in pure liposomes , 2000, Nature Cell Biology.

[17]  Grzegorz Kudla,et al.  The Destabilization of Lipid Membranes Induced by the C-terminal Fragment of Caspase 8-cleaved Bid Is Inhibited by the N-terminal Fragment* , 2000, The Journal of Biological Chemistry.

[18]  P. Krammer,et al.  CD95's deadly mission in the immune system , 2000, Nature.

[19]  Roger Y. Tsien,et al.  Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis , 2000, Nature Cell Biology.

[20]  C. Harris,et al.  Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. , 2000, Mutation research.

[21]  Ximena Opitz-Araya,et al.  Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization , 2002, Science.

[22]  D. Green,et al.  The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis , 1997, Science.

[23]  P. Vandenabeele,et al.  Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation , 2001, Cell Death and Differentiation.

[24]  Luca Scorrano,et al.  A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. , 2002, Developmental cell.

[25]  X. Roucou,et al.  Bid induces cytochrome c-impermeable Bax channels in liposomes. , 2002, The Biochemical journal.

[26]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[27]  H. Nakayama,et al.  A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. , 2001, Molecular cell.

[28]  F Gambale,et al.  Inhibition of Bax channel-forming activity by Bcl-2. , 1997, Science.

[29]  H. Horvitz,et al.  C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2 , 1994, Cell.

[30]  T. Chittenden,et al.  A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. , 1995, The EMBO journal.

[31]  S. Korsmeyer,et al.  A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast , 2001, The Journal of cell biology.

[32]  Robert L Moritz,et al.  Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins , 2000, Cell.

[33]  A. Strasser,et al.  The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. , 1999, Molecular cell.

[34]  Marcel Leist,et al.  Four deaths and a funeral: from caspases to alternative mechanisms , 2001, Nature Reviews Molecular Cell Biology.

[35]  Xiaodong Wang,et al.  Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c , 1996, Cell.

[36]  K. Franssila,et al.  Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. , 1995, Cancer research.

[37]  J C Reed,et al.  IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases , 1998, The EMBO journal.

[38]  T. Chittenden,et al.  Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Cote,et al.  Primers for mitochondrial DNA replication generated by endonuclease G. , 1993, Science.

[40]  S. Korsmeyer,et al.  Biochemical and Genetic Analysis of the Mitochondrial Response of Yeast to BAX and BCL-XL , 2000, Molecular and Cellular Biology.

[41]  T. Mak,et al.  Apaf1 Is Required for Mitochondrial Pathways of Apoptosis and Brain Development , 1998, Cell.

[42]  Junying Yuan,et al.  Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis , 1998, Cell.

[43]  J. Martinou,et al.  Bax Is Present as a High Molecular Weight Oligomer/Complex in the Mitochondrial Membrane of Apoptotic Cells* , 2001, The Journal of Biological Chemistry.

[44]  Y. Uchiyama,et al.  Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[46]  A. Hara,et al.  Localization of Bax and Bcl-2 proteins, regulators of programmed cell death, in the human central nervous system , 1996, Virchows Archiv.

[47]  M. Peter,et al.  Differences between CD95 type I and type II cells detected with the CD95 ligand [1] , 1999 .

[48]  M. Priault,et al.  Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. , 1999, European journal of biochemistry.

[49]  Y. Tsujimoto,et al.  Essential Role of Voltage-Dependent Anion Channel in Various Forms of Apoptosis in Mammalian Cells , 2001, The Journal of cell biology.

[50]  G. Kroemer,et al.  The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins , 1998, The Journal of experimental medicine.

[51]  T. Mak,et al.  Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death , 2001, Nature.

[52]  D. Green,et al.  Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL* , 1999, The Journal of Biological Chemistry.

[53]  Z. Oltvai,et al.  BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax , 1994, Nature.

[54]  Jean-Claude Martinou,et al.  Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions , 1998, The Journal of cell biology.

[55]  Christian Renken,et al.  Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release , 2000, The Journal of cell biology.

[56]  C. Hackenbrock,et al.  Multiple conformations of physiological membrane-bound cytochrome c. , 1998, Biochemistry.

[57]  I. Ferrer,et al.  Bcl-2 and Bax protein expression in Alzheimer’s disease , 1998, Acta Neuropathologica.

[58]  Guido Kroemer,et al.  Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[59]  R. Moritz,et al.  HtrA2 Promotes Cell Death through Its Serine Protease Activity and Its Ability to Antagonize Inhibitor of Apoptosis Proteins* , 2002, The Journal of Biological Chemistry.

[60]  G. Azzone,et al.  Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. , 1981, The Journal of biological chemistry.

[61]  Sten Orrenius,et al.  Injected cytochrome c induces apoptosis , 1998, Nature.

[62]  D. Brdiczka,et al.  Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. , 1998, Biochimica et biophysica acta.

[63]  C. Lucchinetti,et al.  Bcl‐2–expressing oligodendrocytes in multiple sclerosis lesions , 1999, Glia.

[64]  D. Luk,et al.  Human HtrA, an Evolutionarily Conserved Serine Protease Identified as a Differentially Expressed Gene Product in Osteoarthritic Cartilage* , 1998, The Journal of Biological Chemistry.

[65]  Masashi Narita,et al.  Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC , 1999, Nature.

[66]  Jay Z. Parrish,et al.  Mitochondrial endonuclease G is important for apoptosis in C. elegans , 2001, Nature.

[67]  Y. Hsu,et al.  Conformation of the Bax C‐terminus regulates subcellular location and cell death , 1999, The EMBO journal.

[68]  P. Gluckman,et al.  Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus , 1997, Brain Research.

[69]  S. Nagata,et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD , 1998, Nature.

[70]  G Waksman,et al.  Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[71]  A. Petros,et al.  Solution structure of the antiapoptotic protein bcl-2 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[72]  John Calvin Reed,et al.  Upregulation of bax protein levels in neurons following cerebral ischemia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[73]  J. Martinou,et al.  Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. , 2000, The Biochemical journal.

[74]  Junying Yuan,et al.  Solution Structure of BID, an Intracellular Amplifier of Apoptotic Signaling , 1999, Cell.

[75]  Y. Hsu,et al.  Bax in Murine Thymus Is a Soluble Monomeric Protein That Displays Differential Detergent-induced Conformations* , 1998, The Journal of Biological Chemistry.

[76]  Gerard I. Evan,et al.  The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant , 2000, Nature Cell Biology.

[77]  Xiaodong Wang,et al.  DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis , 1997, Cell.

[78]  S. Verma,et al.  Phosphorylation of the Pro-apoptotic Protein BIK , 2001, The Journal of Biological Chemistry.

[79]  Emad S. Alnemri,et al.  correction: A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis , 2001, Nature.

[80]  P. Hof,et al.  Differential distribution of presenilin-1, Bax, and Bcl-XL in Alzheimer’s disease and frontotemporal dementia , 1999, Acta Neuropathologica.

[81]  Junying Yuan,et al.  Apoptosis in the nervous system , 2000, Nature.

[82]  Xiaodong Wang,et al.  Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3 , 1997, Cell.

[83]  V. Mootha,et al.  tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. , 2000, Genes & development.

[84]  Sten Orrenius,et al.  Cytochrome c release from mitochondria proceeds by a two-step process , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[85]  S. Korsmeyer,et al.  Solution Structure of the Proapoptotic Molecule BID A Structural Basis for Apoptotic Agonists and Antagonists , 1999, Cell.

[86]  T G Frey,et al.  The internal structure of mitochondria. , 2000, Trends in biochemical sciences.

[87]  P. Nicotera,et al.  Intracellular ATP, a switch in the decision between apoptosis and necrosis. , 1998, Toxicology letters.

[88]  György Hajnóczky,et al.  Rapid Kinetics of tBid-induced Cytochrome c and Smac/DIABLO Release and Mitochondrial Depolarization* , 2002, The Journal of Biological Chemistry.

[89]  M. Crompton,et al.  The mitochondrial permeability transition pore. , 1999, Biochemical Society symposium.

[90]  S. Aquilonius,et al.  Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons , 1999, Acta neurologica Scandinavica.

[91]  X. Liu,et al.  An APAF-1·Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9* , 1999, The Journal of Biological Chemistry.

[92]  S. Korsmeyer,et al.  Regulated Targeting of BAX to Mitochondria , 1998, The Journal of cell biology.

[93]  F. Antonawich Translocation of cytochrome c following transient global ischemia in the gerbil , 1999, Neuroscience Letters.

[94]  J. Zimmerberg,et al.  Bax, but not Bcl-xL, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[95]  P. Nicotera,et al.  Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis , 1997, The Journal of experimental medicine.

[96]  Geng Wu,et al.  Structural basis of IAP recognition by Smac/DIABLO , 2000, Nature.

[97]  R. Virmani,et al.  Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[98]  Yuri Lazebnik,et al.  Identification of Omi/HtrA2 as a Mitochondrial Apoptotic Serine Protease That Disrupts Inhibitor of Apoptosis Protein-Caspase Interaction* , 2002, The Journal of Biological Chemistry.

[99]  Jean-Claude Martinou,et al.  Bid-induced Conformational Change of Bax Is Responsible for Mitochondrial Cytochrome c Release during Apoptosis , 1999, The Journal of cell biology.

[100]  Xiaodong Wang,et al.  Structural and biochemical basis of apoptotic activation by Smac/DIABLO , 2000, Nature.

[101]  N. Tatton Increased Caspase 3 and Bax Immunoreactivity Accompany Nuclear GAPDH Translocation and Neuronal Apoptosis in Parkinson's Disease , 2000, Experimental Neurology.

[102]  T. Tsuruo,et al.  NH2-terminal BH4 Domain of Bcl-2 Is Functional for Heterodimerization with Bax and Inhibition of Apoptosis* , 1999, The Journal of Biological Chemistry.

[103]  A. Herman,et al.  Apoptosis in atherosclerosis: beneficial or detrimental? , 2000, Cardiovascular research.

[104]  B. Zhivotovsky,et al.  Release of adenylate kinase 2 from the mitochondrial intermembrane space during apoptosis , 1999, FEBS letters.

[105]  Nico Tjandra,et al.  Structure of Bax Coregulation of Dimer Formation and Intracellular Localization , 2000, Cell.

[106]  S. Srinivasula,et al.  The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity , 2002, Cell Death and Differentiation.

[107]  Martin Schuler,et al.  Cytochrome C Maintains Mitochondrial Transmembrane Potential and Atp Generation after Outer Mitochondrial Membrane Permeabilization during the Apoptotic Process , 2001, The Journal of cell biology.

[108]  H. Kudo,et al.  Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery , 2002, Journal of gastroenterology and hepatology.

[109]  J. Martinou,et al.  The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event , 1999, The Journal of cell biology.

[110]  M. Peter,et al.  Differences between CD95 type I and II cells detected with the CD95 ligand. , 1999, Cell death and differentiation.

[111]  Xiaodong Wang,et al.  Cytochrome c Deficiency Causes Embryonic Lethality and Attenuates Stress-Induced Apoptosis , 2000, Cell.

[112]  V. Mootha,et al.  A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c , 2001, The EMBO journal.

[113]  R. Hammer,et al.  Adult Apaf-1-deficient mice exhibit male infertility. , 2000, Developmental biology.

[114]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[115]  S. Korsmeyer,et al.  Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis , 1998, The EMBO journal.

[116]  Y. Tsujimoto,et al.  Involvement of the bcl-2 gene in human follicular lymphoma. , 1985, Science.

[117]  G. Kroemer,et al.  NADH Oxidase Activity of Mitochondrial Apoptosis-inducing Factor* , 2001, The Journal of Biological Chemistry.

[118]  Andy J. Minn,et al.  Bcl-xL forms an ion channel in synthetic lipid membranes , 1997, Nature.

[119]  M. V. Vander Heiden,et al.  Role of Oxidative Phosphorylation in Bax Toxicity , 2000, Molecular and Cellular Biology.

[120]  A. Halestrap,et al.  Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury , 1997 .

[121]  John Calvin Reed,et al.  Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. , 1996, Cancer research.

[122]  J C Reed,et al.  Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. , 1998, Science.

[123]  Yi-Te Hsu,et al.  Movement of Bax from the Cytosol to Mitochondria during Apoptosis , 1997, The Journal of cell biology.

[124]  S. Korsmeyer,et al.  Bax suppresses tumorigenesis and stimulates apoptosis in vivo , 1997, Nature.

[125]  J. Martinou,et al.  Bid Induces the Oligomerization and Insertion of Bax into the Outer Mitochondrial Membrane , 2000, Molecular and Cellular Biology.

[126]  J. Hunter,et al.  A Peptide Sequence from Bax That Converts Bcl-2 into an Activator of Apoptosis (*) , 1996, The Journal of Biological Chemistry.

[127]  John Calvin Reed,et al.  Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. , 1993, Cancer research.

[128]  Xiaodong Wang,et al.  Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition , 2000, Cell.

[129]  S. Korsmeyer,et al.  BH3 Domain of BAD Is Required for Heterodimerization with BCL-XL and Pro-apoptotic Activity* , 1997, The Journal of Biological Chemistry.

[130]  Xu Luo,et al.  Endonuclease G is an apoptotic DNase when released from mitochondria , 2001, Nature.

[131]  B. Zhivotovsky,et al.  Role of apoptosis in pancreatic beta-cell death in diabetes. , 2001, Diabetes.

[132]  B. Antonsson,et al.  Bax and heart mitochondria: uncoupling and inhibition of respiration without permeability transition. , 2002, Biochimica et biophysica acta.

[133]  A. Tolkovsky,et al.  Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis , 2001, Current Biology.

[134]  R. J. Clem,et al.  An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif , 1993, Journal of virology.