Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (
MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to
MMP include the pro- and antiapoptotic members of the Bcl-2 family,
proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial
lipids. Intermediate metabolites, redox processes,
sphingolipids, ion gradients,
transcription factors, as well as
kinases and
phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once
MMP has been induced, it causes the release of catabolic
hydrolases and activators of such
enzymes (including those of
caspases) from mitochondria. These catabolic
enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by
ischemia/reperfusion, intoxication with
xenobiotics,
neurodegenerative diseases, or
viral infection also relies on
MMP as a critical event. The inhibition of
MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of
MMP in
tumor cells constitutes the goal of anticancer
chemotherapy.