Target to Mitochondria either in jury or protection Lin GH
Target to Mitochondria either injury or protection Lin GH
Mitochondrial Renaissance 02 ATP Stress Killer ROS or Messenger Death←— Cyto c or Life Fission NO says Yes Fusion Ca2+homeostasis Ca2+signals ER
Mitochondrial Renaissance ATP ROS Death Cyto c or Life Fission Fusion Killer or Messenger ER Ca2+ homeostasis Ca2+ signals O2 Stress NO says Yes
Mitochondrion:Center Stage Cellular Damage Death Recepto Center stage in apoptosis Caspase-8 Gate opens Numerous cell-death stimuli work through the mitochondrion.They cause pro-apoptotic members of BCL-2 closes this gate the BCL-2 family,such as BAX and BAK,to either open new pores or modify existing channels in the mitochondrial membrane, releasing cytochrome c and other proteins that lead to caspase activation and cell death. Death executioner
Numerous cell-death stimuli work through the mitochondrion. They cause pro-apoptotic members of the BCL-2 family, such as BAX and BAK, to either open new pores or modify existing channels in the mitochondrial membrane, releasing cytochrome c and other proteins that lead to caspase activation and cell death. Center stage in apoptosis Death executioner
Primary and secondary signaling pathways in preconditioning PO PI3K PKB mTOR signaling endosome cascade p70s6K GSK eNOS ERK PKC BAD ROS +VDAC◆ MPT Protective K ATP targetm
Primary and secondary signaling pathways in preconditioning Protective target signaling cascade
Extraceilular stimull Death receptor Apoptosis is mediated by two central pathways: Extrinsic(death receptor) Intrinsic(mitochondrial) Genetic inhibition of cardiac myocyte apoptosis reduces infarct size 50%to 70% after I-R. Pharmacological caspase inhibitors reduced infarct size by 21%to 52%. -Cardiac myocyte apoptosis plays a critical role in the pathogenesis of I-R injury. DEATH
Apoptosis is mediated by two central pathways: Extrinsic (death receptor) Intrinsic (mitochondrial) Genetic inhibition of cardiac myocyte apoptosis reduces infarct size 50% to 70% after I-R. Pharmacological caspase inhibitors reduced infarct size by 21% to 52%. → Cardiac myocyte apoptosis plays a critical role in the pathogenesis of I-R injury
Apoptotic stimuli eventually funnel into Bcl-2 proteins Holey Mitochondria CD95 Bid -2 a acl-2 Apoptosis Bcl-2 Family Proteins As Pores PT Pore
Bcl-2 Family Proteins As Pores Holey Mitochondria PT Pore Apoptotic stimuli eventually funnel into Bcl-2 proteins
Anti-apoptotic BH4 8H3 BH1 BH2 TM Bcl-2 Protein Family Bcl-2 B Bcl-xL c Bax multidomain Pro-apoptotic proapoptotics BH3 BH2 TM BH3-only Bad(TM domain missing) proapoptotics TM Bcl-xL complexed with the Bad BH3 domain BH1(red),BH2 (orange),BH3(green),and BH4(yellow) Bcl-(contains BH4 domain)
Bcl-2 Protein Family Bcl-2 Bcl-xL Bax BH1 (red), BH2 (orange), BH3 (green), and BH4 (yellow) multidomain proapoptotics BH3-only proapoptotics
The Bcl-2 Protein Family: andarbitrate n830ne0brae27Tehemeeato56tomdoSE8c Arbiters of Cell Survival (for exampeDNA dar ion and signal induced by eng proceeds primarily through the adaptor FADD,which direct ly activates caspase-8 and largely bypasses the Bcl-2 family C.elegans Mammals Bik EGL-1 Intracellula CED-9 CD95 Plasma membrane cl-2 Bax membrane CED-4 Apaf-1 FADD CED-3 Caspase-9】 caspase-8 Apoptosis Apoptosis Apoptosis 28 AUGUST 1998 VOL 281 SCIENCE www.sciencemag.org
Bcl-2 family Pro-survival Regulation ancho Pro-apoptosis Bal2Subfamily Pore formation Bax]Subfamily Ligand domain BcH2 BH3 M Bax Bcx Bak ☐ Bcl-w a Bok Mcl-1 BH的Subfamily A1 Bik BH3 % NR-13 ☑ B张 BHRF1 Hrk LMW5-HL BNIP3 ORF16 Bim ☐ KS-Bcl-2 Bad E1B-19K Bid CED-9 EGL-1 wider Bcl-2 family.Three subfamilies are i te The a core of val,whereas the e Bax and BH3 BH4 are conserved orts and a Arro unction describ n the text.The (see text compared are ma rese Bc- a tunctiona H human),except pt fo BH3 n,the 9 theirproteinLM-KS-2.and
Bcl-2 family
Multidomain Proapoptotic Bcl-2 Proteins Bax:inactive state in the cytosolresponse to apoptotic stimuli- conformational change-translocation to mitochondria oligomerization,and insertion into OMM-stimulates cyto c release Cytosol 143-3 Cyto Cye Bax plays a critical role in I-R Mitochondrial matrix Mitochondrial matrix injury as illustrated by the Cell survival Apoptosis 50%reductions in infarct size Model for the mechanism of exhibited by isolated hearts action of Bcl-2 family proteins from Bax knockout mice
Multidomain Proapoptotic Bcl-2 Proteins Bax : inactive state in the cytosol → response to apoptotic stimuli→ conformational change → translocation to mitochondria, oligomerization, and insertion into OMM→ stimulates cyto c release Bax plays a critical role in I-R injury as illustrated by the 50% reductions in infarct size exhibited by isolated hearts from Bax knockout mice Model for the mechanism of action of Bcl-2 family proteins