FIGURE 1.

Model for the role of specific complex II inhibition for apoptosis induction by various proapoptotic compounds. Mitochondrial matrix, inner membrane (IM), intermembrane space, outer membrane (OM), and cytosolic space are indicated. A: in healthy cells, complex II serves to funnel electrons derived from the Krebs cycle to the respiratory chain. SDHA-mediated oxidation of succinate to fumarate by the succinate dehydrogenase activity (SDH), as part of the Krebs cycle, provides electrons to complex II. They are transferred to the iron-sulfur centers of the SDHB subunit and finally to the CoQ reduction site the succinate CoQ oxidoreductase (SQR). B: proapoptotic compounds, such as various anticancer drugs, FasL, or tumor necrosis factor (TNF)-α, induce cytosolic (pH_c) and mitochondrial (pH_M) acidification. These pH changes lead to the dissociation of the SDHA/B subunits from complex II and finally to the partial inhibition of the SQR activity without any impairment of the SDH reaction. This specific inhibition leads to complex II uncoupling, superoxide production, and apoptosis. [From Lemarie et al. (260). Reprinted by permission from Macmillan Publishers, Ltd.]