Mitochondria play important roles in the regulation of cell death (i.e., apoptosis and necrosis). They release pro-apoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and caspase-independent cell death, respectively. Another enzyme called poly(ADP-ribose) polymerase 1 (PARP-1), a mediator of programmed necrosis activated by oxidative stress, is an important activator of caspase-independent cell death (Zhang et al. 1994). Overactivation of PARP-1 can induce NAD+ depletion (Ying et al. 2003), leading to the inhibition of SIRT1 as well as inhibition of glycolysis, which in turn would reduce pyruvate supply to the TCA cycle and cause ATP depletion (Ying et al. 2002). The NADH/NAD+ ratio also affects MPT (Alano et al. 2004), which results in the translocation of AIF from mitochondria to the nucleus (Churbanova and Sevrioukova 2008; Yu et al. 2002), ultimately resulting in apoptosis. Thus, an increased NADH/NAD+ ratio caused by alcohol metabolism can influence pro-death and pro-survival signals in the PARP-1–mediated cell-death program.
