Role of Bax and Bak in mitochondrial morphogenesis

Bcl-2 family proteins are potent regulators of programmed cell death. Although their intracellular localization to mitochondria and the endoplasmic reticulum has focused research on these organelles, how they function remains unknown. Two members of the Bcl-2 family, Bax and Bak, change intracellular location early in the promotion of apoptosis to concentrate in focal clusters at sites of mitochondrial division. Here we report that in healthy cells Bax or Bak is required for normal fusion of mitochondria into elongated tubules. Bax seems to induce mitochondrial fusion by activating assembly of the large GTPase Mfn2 and changing its submitochondrial distribution and membrane mobility—properties that correlate with different GTP-bound states of Mfn2. Our results show that Bax and Bak regulate mitochondrial dynamics in healthy cells and indicate that Bcl-2 family members may also regulate apoptosis through organelle morphogenesis machineries.

[1]  D. Chow,et al.  Disruption of Mitochondrial Networks by the Human Cytomegalovirus UL37 Gene Product Viral Mitochondrion-Localized Inhibitor of Apoptosis , 2003, Journal of Virology.

[2]  R. Youle,et al.  Mitochondrial fission in apoptosis , 2005, Nature Reviews Molecular Cell Biology.

[3]  A Mitochondrial Division Apparatus Takes Shape , 2000, The Journal of cell biology.

[4]  R. Youle,et al.  Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis , 2004, The Journal of cell biology.

[5]  Erik E. Griffin,et al.  Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development , 2003, The Journal of cell biology.

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

[7]  Rodrigue Rossignol,et al.  Energy Substrate Modulates Mitochondrial Structure and Oxidative Capacity in Cancer Cells , 2004, Cancer Research.

[8]  K. Mihara,et al.  Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity , 2004, Journal of Cell Science.

[9]  杉岡 梨恵.  Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis , 2005 .

[10]  H. McBride,et al.  Activated Mitofusin 2 Signals Mitochondrial Fusion, Interferes with Bax Activation, and Reduces Susceptibility to Radical Induced Depolarization*[boxs] , 2005, Journal of Biological Chemistry.

[11]  J. McCaffery,et al.  Structural Basis of Mitochondrial Tethering by Mitofusin Complexes , 2004, Science.

[12]  G. Kroemer,et al.  An Anti-apoptotic Viral Protein That Recruits Bax to Mitochondria* , 2004, Journal of Biological Chemistry.

[13]  R. Youle,et al.  Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Rizzuto,et al.  Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. , 2004, Molecular cell.

[15]  S. Frank,et al.  Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis , 2002, The Journal of cell biology.

[16]  Jean-Claude Martinou,et al.  Breaking the mitochondrial barrier , 2001, Nature Reviews Molecular Cell Biology.

[17]  Jie Wu,et al.  Loss of Bif-1 Suppresses Bax/Bak Conformational Change and Mitochondrial Apoptosis , 2005, Molecular and Cellular Biology.

[18]  J. Shaw,et al.  Mitochondrial dynamics and division in budding yeast. , 2002, Trends in cell biology.

[19]  C. Thompson,et al.  Bax and Bak Independently Promote Cytochrome cRelease from Mitochondria* , 2002, The Journal of Biological Chemistry.

[20]  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.

[21]  Suzanne Cory,et al.  The Bcl-2 family: roles in cell survival and oncogenesis , 2003, Oncogene.

[22]  C. Thompson,et al.  Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. , 2004, Molecular cell.

[23]  R. Youle,et al.  Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. , 2004, Molecular biology of the cell.

[24]  R. Youle,et al.  Endophilin B1 is required for the maintenance of mitochondrial morphology , 2004, The Journal of cell biology.

[25]  Colin Adrain,et al.  Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. , 2006, Molecular cell.

[26]  R. Jagasia,et al.  DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans , 2005, Nature.

[27]  Chi Li,et al.  Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis , 2005, Cell.