Figure 3: Mitochondrial caspase-dependent and caspase-independent mechanisms of apoptosis. Mitochondrial dysfunction leads to the permeabilization of its membranes, which is the first step towards apoptosis. Membrane permeabilization of the outer mitochondrial membrane is driven by the mitochondrial permeability transition pore (MPTP), members of the BCL2 protein family (i.e., BAK/BAX), and mitochondrial lipids such as cardiolipin. More specifically, cardiolipin is associated with BAX recruitment to the outer mitochondrial membrane that triggers membrane permeabilization. For the caspase-dependent mechanism of apoptosis, mitochondrial cytochrome c is released to trigger the formation of the apoptosome complex by binding to, and activating, the apoptotic protease activating factor 1 (Apaf1). This in turn, activates caspase-9 and -3, which leads to the release of CAD from its inhibitor, ICAD, resulting in apoptosis induction. The caspase-independent mechanism of apoptosis involves the mitochondrial release of proapoptotic proteins such as apoptosis-inducing factor (AIF) into the cytosol, whereby it can either directly interact with DNA or potentiate mitochondrial oxidative stress through its release to induce apoptosis.