Figure 21-16 Cellular processes that lead to neuronal apoptosis. Cytochrome c (cyt c), which is normally restricted to the space between the inner and outer mitochondrial membranes, is released in response to mitochondrial injury. Cytochrome c, in combination with apoptosis activating factor (apaf), activates caspase-9 by proteolytic cleavage. Activated caspase-9 then leads to activation of caspase-3. This enzyme cleaves a number of substrates, including those necessary for DNA repair. Within the mitochondria, bax augments and bcl prevents the release of cytochrome c. Cytochrome c release can also be initiated by bid, a substance that is activated by caspase-8 through tumor necrosis factor-α (TNF) signaling. In addition, caspase-8 can directly activate caspase 3. Excessive activation of poly-ADP ribose-polymerase (PARP), an enzyme integral to DNA repair, depletes cellular stores of oxidized nicotinamide adenine dinucleotide (NAD⁺ ). Depletion of NAD⁺ further exacerbates the energy failure because it is central to energy metabolism. ATP, adenosine triphosphate.