Cellular stress occurs when cells encounter conditions that disrupt their normal internal balance (homeostasis), leading to changes in structure and function. This universal phenomenon represents a cell’s reaction to adverse environmental or internal changes.
Sources of Cellular Stress
Cells face a diverse array of factors that can induce a state of stress, originating from both their external environment and internal processes. One prevalent type is oxidative stress, which arises from an imbalance between the production of reactive oxygen species (ROS) and a cell’s ability to neutralize them with antioxidants. These reactive molecules can damage cellular components like DNA, proteins, and lipids.
Temperature extremes also cause cellular stress; heat stress can lead to the denaturation and aggregation of proteins, where proteins lose their proper three-dimensional structure and function. Conversely, cold stress can disrupt cellular metabolism. Nutrient deprivation, such as a lack of essential sugars or amino acids, forces cells to activate survival mechanisms.
Chemical toxins, including heavy metals or pollutants, can interfere with various cellular processes, often by denaturing proteins or causing DNA damage. Mechanical stress, resulting from physical forces like stretching or compression, can also perturb cellular integrity. Endoplasmic reticulum (ER) stress occurs when there is an accumulation of misfolded or unfolded proteins within the ER, an organelle responsible for protein folding and modification. This accumulation can overwhelm the ER’s capacity, triggering a stress response.
How Cells Cope with Stress
Cells detect and respond to stressors to restore balance or adapt. This involves activating signaling pathways that lead to adaptation, repair, or programmed cell death if damage is severe. This stress response is conserved across life forms.
The heat shock response involves increased production of heat shock proteins (HSPs). These HSPs act as molecular chaperones, assisting in correct protein folding and refolding damaged proteins, preventing aggregation. Many HSPs also play a role in routine protein maintenance.
Cells also upregulate antioxidant enzymes as a defense against oxidative stress. These enzymes work to neutralize harmful reactive oxygen species, protecting cellular components from damage.
The unfolded protein response (UPR) activates when misfolded proteins accumulate in the endoplasmic reticulum. The UPR alleviates ER stress by halting general protein synthesis, increasing protein-folding chaperones, and enhancing degradation of severely misfolded proteins.
Cells can initiate autophagy, a process of “self-eating” damaged or dysfunctional cellular components to recycle materials and eliminate harmful structures. If stress is overwhelming and repair mechanisms are insufficient, cells trigger apoptosis, a form of programmed cell death, to remove severely damaged cells.
Cellular Stress and Disease
When cellular stress responses are overwhelmed, chronic, or dysregulated, they contribute to the development and progression of various human diseases. For instance, in neurodegenerative diseases like Alzheimer’s and Parkinson’s, accumulated misfolded proteins play a role. This proteotoxic stress can lead to neuronal dysfunction and cell death, underlying cognitive and motor impairments.
Metabolic disorders such as diabetes are also linked to cellular stress, particularly oxidative stress and ER stress in pancreatic beta cells. This stress can impair insulin secretion and contribute to the death of these cells, disrupting blood sugar regulation.
Cardiovascular diseases, including heart failure and myocardial infarction, involve cellular stress from factors like mitochondrial dysfunction, ER stress, and hypoxia. These stressors can lead to damage and dysfunction of heart muscle cells.
Cellular stress is involved in cancer. While stress responses can initially suppress tumors by eliminating damaged cells or halting division, cancer cells often exploit or adapt these pathways to promote survival, proliferation, and therapy resistance. Chronic ER stress, for example, can promote cancer progression.
Aging is associated with accumulated cellular stress and declining efficiency of stress response mechanisms. This reduced ability to cope contributes to age-related cellular damage and increased disease susceptibility.