Apoptosis and Disease: Unbalancing the Survival Equilibrium

Contrary to what might be common sense, the ordered development and maintenance of multicellular organisms not only requires adequate nutrient supply and a flourishing growth potential, but also relies on complex mechanisms of cell suicide. In fact, both tissue sculpting during embryogenesis and their homeostatic regulation in adulthood are the outcome of a dynamic competition between cell proliferation and death, and a network of signals has evolved to induce and keep under a tight control the process of cell elimination. In addition, cells damaged by diverse noxious agents must be efficiently cleared away through a regulated death program to avoid lethal dysfunctions. Accordingly, cells have developed a variety of molecular controllers that sense every potentially harmful metabolic change, damage or genetic abnormality. The unifying response to all these unbalancing or stressful conditions is the activation of a form of programmed cell death termed apoptosis. Apoptotic cells utilize a well-defined biochemical machinery to orderly dismantle their architecture, and become endowed with stereotypical morphological changes which ultimately lead to their engulfment by phagocytic cells. Apoptosis signaling can be grossly subdivided in an initiator phase, which depends either on death receptor activation or on intracellular insults, and in an execution phase, whose biochemical hallmark is the activation of proteases termed caspases. In between these two extremes, a sophisticated system composed by molecular checks and balances determines whether a cell is committed to survive or to die. This final output depends on several integrated parameters, such as the transcriptional regulation of apoptosis inducers or brakes and their subcellular distribution and interactions. In recent years, the comprehension of the molecular bases of apoptosis allowed the identification of an articulated network of crosstalks between the death regulators and signaling pathways that coordinate biological processes such as cell cycle and proliferation. Disturbances in the fine tuning of this intricate death/survival equilibrium result either in an uncontrolled growth or in an excessive degeneration of tissues, leading to a variety of diseases, including cancer, neurodegenerative and autoimmunity disease. Further layers of complexity are added by the finding that other forms of cell death, spanning from autophagy to necrosis through a variety of ill-defined intermediate conditions, are relevant in defined physiologic and pathologic settings. A deep understanding of the mechanisms that regulate the apoptotic machinery, its interactions with other transduction pathways and how these orchestrate the fate of the cell is therefore pivotal for the development of drugs that reinstate the appropriate apoptotic response, either where it is lacking, as in cancer, or where it is exacerbated, as in neurodegenerative diseases