14.1 Overview of Recovery from Cellular Stress [in progress]

Many of the stress tolerance mechanisms this textbook has discussed so far are focused on preventing damage to macromolecules and cellular components when exposed to stressors. However, in many cases damage can occur during stress. For example, a stress-tolerant organism may experience damage to its cellular components if the intensity of stress is high. To continue to tolerate such as stress, that stress-tolerant organism must be able to recover from the damage. If recovery is not possible, the damage may lead to organism death or reduction in fitness. For example, freeze-intolerant organisms likely die following freezing because substantial damage occurs during freezing and thawing, and that damage is not repaired post-thaw.

When macromolecules and cellular components are damaged due to stress, there are several possible cellular responses. If the damage is mild, repair of the damage is often possible in stress-tolerant organisms. If the damage is extreme, some macromolecule types can be replaced while others cannot. If damage is irreparable and irreplaceable, that damage may initiate cell death. The next few sections will discuss which of these outcomes is more likely when each of the major macromolecule types is damaged: repair, replacement, or cell death?

DNA damage

A number of factors can cause DNA damage, such as exposure to UV light, some chemicals, and errors in normal cellular processes like DNA replication (Figure 14.2). Mild DNA damage can be caused by oxidative stress. Reactive oxygen species (ROS) can cause DNA damage in the form of double-stranded breaks as a result of ROS-induced oxidation of guanine nucleotides. This oxidized guanine (8-oxoguanine) can be mis-paired with adenine, causing double-stranded breaks after DNA replication.

Mild damage to DNA can often be repaired (providing the cell has sufficient resources; Chapter 14.2), but extreme damage to DNA cannot. Chromosomal DNA is irreplaceable, so cells work hard to prevent irreparable damage to this macromolecule. Mild DNA damage includes single nucleotide changes, in which one nucleotide is damaged or swapped for another, and single-stranded breaks, which is damage to one strand of DNA’s double-stranded structure. Damage to both of the strands in a DNA molecule, called a double-stranded break, is considered more severe damage and usually cannot be repaired very accurately. Extensively damaged DNA cannot be replaced, and accumulation of damaged DNA will often initiate cell death (Chapter 14.5).

Figure 14.2. Some of the stressors that can cause damage to DNA, and their various mechanism of repair. [copyright – likely need to replace]

Lipid and membrane damage

Multiple stressors can damage membranes and their lipids. One form of mild damage to lipids can be due to oxidative stress. In oxidative stress, lipid oxidation leads to the formation of lipid peroxides (Figure 14.3), which are highly reactive molecules that can cause damage to other biomolecules. Damage to lipids as a result of oxidative stress can in turn damage phospholipid membranes. Extreme temperatures cause phase changes in membranes; warm temperatures cause membranes to become too fluid, while cold temperatures cause membranes to enter gel phase and become very rigid, both of which can cause breaks in the membrane. In addition, ice crystals formed during the freeze-thaw process can puncture cell membranes or cause them to rupture. While mild damage to lipids can sometimes be repaired, it is more challenging for the cell to repair damaged membranes (Chapter 14.2). New lipids can be synthesized to help make new membranes, e.g., to replace damaged organelles (Chapter 14.3). However, if extensive damage to the plasma membrane occurs, the cell will usually die, e.g. via necrosis (Chapter 14.5).

Figure 14.3. Mild oxidative stress can lead to lipid oxidation. Lipid peroxides and lipid peroxyl radicals are themselves ROS (see Chapter 10), which can cause additional damage to other molecules. If these lipid peroxides are part of membrane phospholipids, damage to membranes can occur.

Protein damage

Proteins can be damaged by oxidative stress, osmotic stress, extreme temperature stress, and freezing. Exposure to ROS can cause protein misfolding due to oxidation of the amino acids cysteine and methionine, as well as carbonylation of the peptide backbone (Figure 14.4A). Osmotic stress and temperature stress can cause protein denaturation and aggregation (Figure 14.4B). Freezing stress can potentially cause protein damage due to the oxidative, osmotic, and low temperature stress that are associated with freezing and thawing (see Chapter 13). Denatured proteins can often be refolded (Chapter 14.2). However, if proteins are irreparably damaged, they will most likely be broken down to recycle their amino acids into the synthesis of replacement proteins (Chapter 14.3). Protein damage is a key initiator of cellular stress response (Chapter 14.4) to initiate repair and recovery of many cellular components.

Figure 14.4 (A) Several components of a polypeptide can be oxidized via ROS, including amino acids (e.g., methionine, cysteine) the carbonyl groups along the polypeptide backbone (carbonylation). This oxidation, if left unrepaired, can lead to protein misfolding. (B) Unfolded or misfolded proteins (which can be caused by a variety of stressors) can combine to form large aggregates.