Control of mitochondrial apoptosis by the Bcl-2 family

Programmed cell death, or apoptosis, is important for the development and homeostasis of tissues. Too little cell death can result in autoimmune diseases or cancer, whereas excessive cell death can lead to debilitating degenerative diseases of the heart or nervous system. The realization that apoptosis was genetically controlled first arose when it was observed that certain mutants of the model organism Caenorhabditis elegans caused failure of apoptosis in cells that normally undergo this process during development (Hengartner et al., 1992). Subsequently, it was found that proteins that are encoded by the mutant genes discovered in C. elegans shared homology with mammalian proteins, including B-cell CLL/lymphoma 2 (Bcl-2) (Hengartner and Horvitz, 1994). Further study in mammals revealed that there is an intrinsic apoptotic pathway that involves the mitochondria and an extrinsic apoptotic pathway that involves death receptors. The mitochondrial pathway of apoptosis in mammals, on which this poster article is focused, is regulated by members of the Bcl-2 family of proteins. Proteins of the Bcl-2 family have either pro- or anti-apoptotic activities and regulate the mitochondrial pathway of apoptosis by controlling the permeabilization of the outer mitochondrial membrane. In response to many types of stress or damage, certain members of the Bcl-2 family, known as BH3-only proteins (see below), are activated. Certain BH3-only proteins cause the activation of the pro-apoptotic proteins Bcl-2-associated X protein (Bax) or Bcl-2 antagonist/killer-1 (Bak) at the mitochondrion. Activated Bax and Bak homo-oligomerize and participate in the formation of pores in the outer mitochondrial membrane through which pro-apoptotic molecules escape, including second mitochondria-derived activator of caspase (Smac) (also known as Diablo) and cytochrome c. Release of cytochrome c leads to the activation of caspases, which are proteases that cleave key cellular proteins. This leads to many of the morphological characteristics of apoptosis, including condensed nuclei, DNA ladderin

Loss of Mcl-1 Protein and Inhibition of Electron Transport Chain Together Induce Anoxic Cell Death

How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1β, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(−)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho(−)] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X(L)/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X(L)/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X(L)/Bcl-2 proteins