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Figure 1. Two modes of mitochondrially controlled initiator caspase-9 activation.

The prevailing model (left) features apoptosome (Apaf-1/(d)ATP/cytochrome c/procaspase-9). The complex is assembled through the mitochondrial damage characterized by the fall of the inner membrane potential (Delta-psi-m), release of cytochrome c, and matrix swelling. Apoptosis by staurosporine may represent this model.

Others and we detected active form caspase-9, as well as procaspase-9, in the intermembrane spacce of the mitochondria before the onset of apoptosis. The hypo-Delta-psi-m condition indicates partial dysfunction of the electron transfer system (respiratory chain) tightly assocaited with the redox regulatory system. Under the oxidative condition, the mitochondrion may activate caspase-9 and release it outside .

Katoh I, Tomimori Y, Ikawa Y, Kurata S. J Biol Chem. 2004 Apr 9;279(15):15515-23.

Figure 2. Proposed mechanism of the intra-mitochondrial capase-9 activation: involvement of the mitochondrial metabolic and respiratory systems.

Biochemical studies by others uniquivocally showed that the procaspase-9 molecules can auto-activate by self-dimerization in concentrated solutions or by the aid of kosmotropes, salts that induce protein folding.

Physiological stimuli including oxidative and nitrosative stresses impair the mitochondrial metablic and respiratory chain reactions. Hypo-polarization of the inner membrane (Hypo-Delta-psi-m) is accompanied by ROS overproduction, ATP depletion and accumulation of citrate, a kosmotrope, known to induce caspase-9 dimerization/activation.

Katoh I, Sato S, Fukunishi N, Yoshida H, Imai T, Kurata S. Cell Res. 2008 Dec;18(12):1210-9.