Regulated cell death and adaptive stress responses

Abstract

Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis.

Keywords: Apoptosis; Autophagy; Ferroptosis; Mitochondrial permeability transition; Necroptosis.

Fig. 1

General organization of stress responses in modern eukaryotes. Eukaryotic cells generally respond to perturbations of intracellular or extracellular homeostasis by simultaneously activating a rapid mechanism of adaptation, relying on ready-made components and post-translational modifications, as well as a transcription-dependent system, which comes into action, if needed, to support adaptation over time. Alongside, stress sensors also dispatch signals that inhibit regulated cell death (RCD). If adaptation fails and homeostasis cannot be recovered, however, the signals dispatched by stress sensors become lethal, and cells undergo RCD

Fig. 2

Alternative models for the transition between the adaptive and lethal phase of stress responses. At least theoretically, failing stress responses can result in the activation of regulated cell death (RCD) via two mechanisms. a Stress sensors initially dispatch RCD-inhibiting as well as RCD-promoting signals, and RCD intervenes when the latter overcome the former. b Stress sensors initially dispatch RCD-inhibiting signals, which cease as adaptation fails. Alongside, stress sensors become able to dispatch RCD-promoting signals, which eventually cause RCD