References 1. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116: 205–219. 2. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59. 3. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, et al. (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730. 4. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, et al. (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6: 1389–1399. 5. Ow YP, Green DR, Hao Z, Mak TW (2008) Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 9: 532–542. 6. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11: 621–632. 7. Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, et al. (2006) Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol. 8. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, et al. (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525–535. 9. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, et al. (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183–192. 10. Ren D, Tu HC, Kim H, Wang GX, Bean GR, et al. (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330: 1390–1393. 11. Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, et al. (2009) Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36: 487–499. 12. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, et al. (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315: 856–859. 13. Merino D, Giam M, Hughes PD, Siggs OM, Heger K, et al. (2009) The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J Cell Biol 186: 355–362. 14. Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, et al. (2011) A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria. Mol Cell. 15. Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777: 946–952. 16. Tsujimoto Y, Shimizu S (2007) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12: 835–840. 17. Zhivotovsky B, Galluzzi L, Kepp O, Kroemer G (2009) Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery. Cell Death Differ 16: 1419–1425. 18. Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, et al. (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102: 12005–12010. 19. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, et al. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658. 20. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, et al. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662. 21. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, et al. (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280: 18558–18561. 22. Mizuta T, Shimizu S, Matsuoka Y, Nakagawa T, Tsujimoto Y (2007) A Bax/ Bak-independent mechanism of cytochrome c release. J Biol Chem 282: 16623– 16630. 23. Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome. Mol Cell 35: 551–561. 24. Hetz C, Martinon F, Rodriguez D, Glimcher LH (2011) The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1{alpha}. Physiol Rev 91: 1219–1243. 25. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13: 89–102. 26. Woehlbier U, Hetz C (2011) Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci 36: 329–337. 27. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, et al. (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300: 135–139. 28. Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, et al. (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162: 59–69. 29. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, et al. (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312: 572–576. A BAX/BAK/CypD-Independent Intrinsic Death Pathway 30. Hetz CA (2007) ER Stress Signaling and the BCL-2 Family of Proteins: From Adaptation to Irreversible Cellular Damage. Antioxid Redox Signal 9: 2345– 2356. 31. Heath-Engel HM, Chang NC, Shore GC (2008) The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene 27: 6419– 6433. 32. Rodriguez JM, Glozak MA, Ma Y, Cress WD (2006) Bok, Bcl-2-related Ovarian Killer, Is Cell Cycle-regulated and Sensitizes to Stress-induced Apoptosis. J Biol Chem 281: 22729–22735. 33. Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ (1997) Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and hetero- dimerizes with selective anti-apoptotic Bcl-2 family members. Proc Natl Acad Sci U S A 94: 12401–12406. 34. Suominen JS, Yan W, Toppari J, Kaipia A (2001) The expression and regulation of Bcl-2-related ovarian killer (Bok) mRNA in the developing and adult rat testis. Eur J Endocrinol 145: 771–778. 35. Heath-Engel HM, Chang NC, Shore GC (2008) The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene 27: 6419– 6433. 36. Roy SS, Madesh M, Davies E, Antonsson B, Danial N, et al. (2009) Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell 33: 377–388. 37. Ren D, Tu HC, Kim H, Wang GX, Bean GR, et al. (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330: 1390–1393. 38. Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, et al. (2009) BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell 33: 679–691. 39. Rodriguez D, Zamorano S, Lisbona F, Rojas-Rivera D, Cubillos-Ruiz J, et al. (2012) BH3-only proteins are part of a regulatory network that control the sustained signaling of the Unfolded Protein Response sensor IRE1. EMBO J. In press. 40. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, et al. (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664–666. 41. Kim I, Shu CW, Xu W, Shiau CW, Grant D, et al. (2009) Chemical biology investigation of cell death pathways activated by endoplasmic reticulum stress reveals cytoprotective modulators of ASK1. J Biol Chem 284: 1593–1603. 42. Kim AJ, Shi Y, Austin RC, Werstuck GH (2005) Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. J Cell Sci 118: 89–99. 43. Song L, De Sarno P, Jope RS (2002) Central role of glycogen synthase kinase- 3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem 277: 44701–44708. 44. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, et al. (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18: 3066–3077. 45. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21: 1249–1259. 46. Lin JH, Li H, Zhang Y, Ron D, Walter P (2009) Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One 4: e4170-. 47. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, et al. (2007) ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim. Cell 129: 1337–1349. 48. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897–904. 49. Rojas-Rivera D, Armisen R, Colombo A, Martinez G, Eguiguren AL, et al. (2012) TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis. Cell Death Differ. 50. Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, et al. (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci 31: 966–978. 51. Keinan N, Tyomkin D, Shoshan-Barmatz V (2010) Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. Mol Cell Biol 30: 5698–5709. 52. Scharstuhl A, Mutsaers HA, Pennings SW, Russel FG, Wagener FA (2009) Involvement of VDAC, Bax and ceramides in the efflux of AIF from mitochondria during curcumin-induced apoptosis. PLoS One 4: e6688-. 53. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, et al. (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7: 1166–1173. 54. Ow YP, Green DR, Hao Z, Mak TW (2008) Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 9: 532–542. 55. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, et al. (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280: 18558–18561. 56. Caro-Maldonado A, Tait SW, Ramirez-Peinado S, Ricci JE, Fabregat I, et al. (2010) Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells. Cell Death Differ 17: 1335–1344. PLoS ONE | www.plosone.org 15 June 2012 | Volume 7 | Issue 6 | e37782