Autophagy and the Integrated Stress Response

Autophagy and the Integrated Stress Response

Eukaryotic cells must adapt continuously to fluctuations in external conditions, including physical parameters such as temperature and ultraviolet light; chemical cues such as ion concentrations, pH, oxygen tension, redox potentials, and metabolite concentrations; extracellular signals such as contact-dependent signals, hormones, cytokines, and neurotransmitters; and microbial pathogens. Beyond a certain threshold, such fluctuations are considered “stresses,” meaning that the cell's response to this stress determines whether it can function properly and survive.

Mitochondrial Damage

Cells must remove damaged mitochondria to prevent the accumulation of ROS. This process of mitochondrial quality control is mediated by mitophagy, the selective autophagic removal of mitochondria. Considerable advances have been made in understanding the mechanisms by which damaged mitochondria are targeted for autophagy, as well as the functional significance of mitochondrial quality control in preventing aging, neurodegenerative diseases, and other pathologies.

In response to potentially lethal stress or damage, mitochondrial membranes can be permeabilized through multiple distinct biochemical routes. Indeed, mitochondrial membrane permeabilization (MMP) constitutes one of the hallmarks of imminent apoptotic or necrotic cell death

Integration of Autophagy and Other Cellular Stress Responses

The integration of autophagy and other cellular stress responses can be conceptualized in the framework of three broad concepts. First, a single type of stress stimulus elicits a variety of signals that trigger distinct cellular responses (one of which is autophagy) that cooperate for the sake of optimal cellular repair and adaptation. Second, distinct stress responses are often integrated through the ability of a single molecular event to stimulate multiple adaptive pathways (one of which is autophagy). Third, distinct cellular stress response pathways, including autophagy, mutually control other stress response pathways.

(1) redox stress, which induces transcriptional reprogramming through HIF, NF-κB, and p53 activation; elicits the UPR; and stimulates both general and selective autophagy; (2) hypoxia, which induces adaptive responses including the transcriptional activation of angiogenic and cytoprotective cytokines in parallel with autophagy stimulation; and (3) DNA damage, which elicits nuclear p53 translocation, cell-cycle checkpoint activation, cell-cycle arrest, and autophagy.

Key Cellular Stress Response Networks(A) Particular stress stimuli (e.g., oxidative damage, hypoxia or anoxia, nutrient starvation, ER stress) can elicit different responses that cooperate to achieve optimal cellular repair and adaptation. A diverse range of stressors activate interconnected cytoprotective mechanisms able to modulate autophagy at different levels, such as transcriptional reprogramming, protein modifications (phosphorylation, acetylation, etc.), or cell-cycle modulation.(B) Autophagy inhibition and stress. Autophagy impairment leads to the accumulation of damaged proteins and organelles, which in turn can elicit cellular stress. Moreover, disabled autophagy can increase the abundance of p62, resulting in an enhanced activity of NF-κB, which leads to enhanced inflammation. By contrast, p62 accumulation leads to the activation of Nrf2 transcription factor and in a consequent increase in the expression of stress response enzymes.(C) Mutual exclusion between autophagy and apoptosis. Autophagy, as a cytoprotective pathway, eliminates potential sources of proapoptotic stimuli such as damaged mitochondria, thereby setting a higher threshold against apoptosis induction. By contrast, the apoptosis-associated activation of proteases such as calpain and caspase-3 may destroy autophagy-specific factors (Atg4D, Beclin 1, or Atg5), thereby suppressing autophagy.

Hypoxia and Anoxia

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HIF is a heterodimer of a constitutive β subunit and an oxygen-regulated α subunit that only becomes stabilized (and hence expressed) when oxygen concentration declines below a threshold of ∼5%. Upon moderate hypoxia (1%–3% oxygen), HIF activates the transcription of BNIP3 and BNIP3L (NIX), two BH3-only proteins that can disrupt the inhibitory interaction between Beclin 1 and Bcl-2.

Overview of Selected Stress Pathways that Induce AutophagyThe mechanisms involved in autophagy induction by hypoxia or anoxia (A), increased oxidative damage (reactive oxygen species, ROS) (B), perturbation of the p53 system (C), or mitochondrial dysfunction (D) are represented schematically.

Overview of the Major Signal Transduction Pathways that Regulate Autophagy in Response to StarvationA summary of starvation-induced proautophagic signaling (A) is followed by a schematic overview of the signaling cascades involving sirtuin-1 and Foxo 3a (B), AMPK (C), and mTORC1 (D).