Apoptosis and liver diseases: recent concepts of mechanism and significance.

Apoptosis, or programmed cell death, is a highly conserved mechanism that plays an essential role in numerous normal developmental and regulatory processes and disease states. It is mediated by a variable interaction among several components of the cell, including cell surface death receptors, the caspase cascade, mitochondrial metabolism and energetics, and the cytoskeleton. Even in those instances in which cell surface death receptors play a role, mitochondria are often central to the process, not only in mediating the death program, but in initiating it as well. In regard to mitochondrial involvement, a key role is hypothesized for an interaction among AMP-activated protein kinase, cytoskeletal intermediate filaments, and mitochondrial oxidation of fatty acids. This proposed interaction may be a critical element in the pathogenesis of intramitochondrial oxidative stress, diminished inner membrane potential (delta psi(m)), and other mitochondrial changes that contribute to cell death. Apoptosis may participate in a wide variety of disease processes, ranging from chemical and physical injury to viral infection and cancer, but its mechanistic and functional relationship to these conditions remains incompletely understood. Despite this, an understanding of the mechanisms involved and of the identity of potential pharmacologic targets is increasing, and warrants an optimistic view of their potential for clinical application.