Mitochondria: pharmacological manipulation of cell death

Abstract

Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.

Figure 1

Molecular mechanisms of MOMP. The proposed models of MOMP leading to cytochrome c release are represented. (i) Bax pore. Bax or Bak forms a pore in the MOM after activation by a BH3-only protein such as Bid. (ii) PT pore opening. Opening of the PT pore allows an influx of water and ions into the matrix, causing matrix swelling; this leads to rupture of the MOM, releasing IMS proteins such as cytochrome c. MIM, mitochondrial inner membrane; PBR, peripheral benzodiazepine receptor.

Figure 2

Models of Bcl-2–family function at the mitochondrion during apoptosis. (A) The traditional simple rheostat model assumes that the antiapoptotic Bcl-2–family proteins antagonize the BH3-only proteins, in an equal and opposite manner. (B) Recent results suggest a more inclusive and detailed model, which we term the “switched rheostat.” Bax and Bak are the effectors of MOMP. Certain BH3-only proteins (“direct activators”) and p53 switch on Bax (and possibly Bak) directly and are antagonized by antiapoptotic Bcl-2–family proteins. Other BH3-only proteins (“derepressors”) do not activate Bax directly but act by antagonizing the antiapoptotic family members, thereby freeing the direct activators to trigger Bax/Bak–induced MOMP. The dashed lines indicate that the derepressor BH3-only proteins have differing specificities for antiapoptotic family members.