Cell damage can result in death of individual cells, tissue or organ failure and/or death of the organism. Harmful molecules are continually bombarding the human body, such as free radicals, by-products of energy production. These damage the proteins, fats and DNA that make up cells. When young, the body is able to repair most cellular damage. As it ages, the repair process becomes less efficient.
- Physical agents such as heat or radiation can damage a cell by literally cooking or coagulating their contents.
- Impaired nutrient supply, such as lack of oxygen or glucose, or the production of adenosine triphosphate (ATP) may deprive the cell of essential materials needed to survive.
- DNA damage: In human cells, both normal metabolic activities and environmental factors such as ultraviolet light and other radiations can cause DNA damage, resulting in as many as one million individual molecular lesions per cell per day.
- Membrane damage: damage to the cell membrane disturbs the state of cell electrolytes, e.g. calcium, which when constantly increased, induces apoptosis.
Types of damage
Some cell damage can be reversed once the stress is removed or if compensatory cellular changes occur. Full function may return to cells but in some cases a degree of injury will remain.
Cellular swelling may occur due to cellular hypoxia, which damages the sodium-potassium membrane pump; it is reversible when the cause is eliminated. Cellular swelling is the first manifestation of almost all forms of injury to cells. When it affects many cells in an organ, it causes some pallor, increased turgor, and increase in weight of the organ. On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum. This pattern of non-lethal injury is sometimes called hydropic change or vacuolar degeneration. The ultrastructural changes of reversible cell injury include: • Blebbing • Blunting • distortion of microvilli • creation of myelin figures • loosening of intercellular attachments • mitochondrial changes • dilation of the endoplasmic reticulum
Cell has been damaged and is unable to adequately metabolize fat. Small vacuoles of fat accumulate and become dispersed within cytoplasm. When mild, fatty change may have no effect on cell function but more severe fatty change may impair cellular function. In the liver, the enlargement of hepatocytes due to fatty change may compress adjacent bile canaliculi, leading to cholestasis. Depending on the cause and severity of the lipid accumulation, fatty change is generally reversible.
Progressive failure of essential metabolic and structural cell components usually in the cytoplasm. Necrosis generally involves a group of contiguous cells or occurs at the tissue level. Such progressive deterioration of the cell rapidly leads to cell death.
Process of self-destruction of the cell nucleus. It is not contiguous, but instead the dying cells are scattered throughout the tissue. In apoptosis the cells shrink from a decrease of cytosol and the nucleus, the organelles appear normal. The cell disintegrates into fragments referred to as apoptotic bodies. Apoptosis happens to everybody, in the average adult between 50 and 70 billion cells die each day due to apoptosis. Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. Hyperactive apoptosis can lead to neurodegenerative diseases, hematologic diseases, and tissue damage.
When a cell is damaged the body will try to repair or replace the cell to continue normal functions. If a cell dies the body will remove it and replace it with another functioning cell, or fill the gap with connective tissue to provide structural support for the remaining cells. The goal of the repair process is to fill the gap caused by the damaged cells to regain structural continuity. Normal cells try to regenerate the damaged cells but this cannot always happen.
Regeneration of parenchyma cells, or the functional cells, of an organism. The body can make more cells to replace the damaged cells keeping the organ or tissue intact and fully functional.
When a cell cannot be regenerated the body will replace it with stromal connective tissue to maintain tissue/organ function. Stromal cells are the cells that support the parenchymal cells in any organ. Fibroblasts, immune cells, pericytes, and inflammatory cells are the most common types of stromal cells.
DNA damage and repair
DNA damage (or RNA damage in the case of some virus genomes) appears to be a fundamental problem for life. As noted by Haynes, the subunits of DNA are not endowed with any peculiar kind of quantum mechanical stability, and thus DNA is vulnerable to all the “chemical horrors” that might befall any such molecule in a warm aqueous medium. These chemical horrors are DNA damages that include various types of modification of the DNA bases, single- and double-strand breaks, and inter-strand cross-links (see DNA damage (naturally occurring). DNA damages are distinct from mutations although both are errors in the DNA. Whereas DNA damages are abnormal chemical and structural alterations, mutations ordinarily involve the normal four bases in new arrangements. Mutations can be replicated, and thus inherited when the DNA replicates. In contrast, DNA damages are altered structures that cannot, themselves, be replicated.
Several different repair processes can remove DNA damages (see chart in DNA repair). However, those DNA damages that remain un-repaired can have detrimental consequences. DNA damages may block replication or gene transcription. These blockages can lead to cell death. In multicellular organisms, cell death in response to DNA damage may occur by a programmed process, apoptosis. Alternatively, when a DNA polymerase replicates a template strand containing a damaged site, it may inaccurately bypass the damage and, as a consequence, introduce an incorrect base leading to a mutation. Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR).
In both prokaryotes and eukaryotes, DNA genomes are vulnerable to attack by reactive chemicals naturally produced in the intracellular environment and by agents from external sources. An important internal source of DNA damage in both prokaryotes and eukaryotes is reactive oxygen species (ROS) formed as byproducts of normal aerobic metabolism. For eukaryotes, oxidative reactions are a major source of DNA damage (see DNA damage (naturally occurring) and Sedelnikova et al.). In humans, about 10,000 oxidative DNA damages occur per cell per day. In the rat, which has a higher metabolic rate than humans, about 100,000 oxidative DNA damages occur per cell per day. In aerobically growing bacteria, ROS appear to be a major source of DNA damage, as indicated by the observation that 89% of spontaneously occurring base substitution mutations are caused by introduction of ROS-induced single-strand damages followed by error-prone replication past these damages. Oxidative DNA damages usually involve only one of the DNA strands at any damaged site, but about 1-2% of damages involve both strands. The double-strand damages include double-strand breaks (DSBs) and inter-strand crosslinks. For humans, the estimated average number of endogenous DNA DSBs per cell occurring at each cell generation is about 50. This level of formation of DSBs likely reflects the natural level of damages caused, in large part, by ROS produced by active metabolism.
Repair of DNA damages
Five major pathways are employed in repairing different types of DNA damages. These five pathways are nucleotide excision repair, base excision repair, mismatch repair, non-homologous end joining and homologous recombinational repair (HRR) (see chart in DNA repair) and reference. Only HRR can accurately repair double strand damages, such as DSBs. The HRR pathway requires that a second homologous chromosome be available to allow recovery of the information lost by the first chromosome due to the double-strand damage.
DNA damage appears to play a key role in mammalian aging, and an adequate level of DNA repair promotes longevity (see DNA damage theory of aging and reference.). In addition, an increased incidence of DNA damage and/or reduced DNA repair cause an increased risk of cancer (see Cancer, Carcinogenesis and Neoplasm) and reference). Furthermore the ability of HRR to accurately and efficiently repair double-strand DNA damages likely played a key role in the evolution of sexual reproduction (see Evolution of sexual reproduction and reference.  In extant eukaryotes, HRR during meiosis provides the major benefit of maintaining fertility.
- Klaassen, C.D., Ed.: Casarett and Doull's Toxicology: The Basic Science of Poisons. Sixth Edition, McGraw-Hill, 2007 .
- Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, WH Freeman: New York, NY. 5th ed., p. 963
- Hayes, A.W., Ed.: Principles and Methods of Toxicology Fourth Edition, Raven Press, New York, 2001 and 5th edition (2008).
- "Cellular Swelling." Humpath.com-Human Pathology. Humpath.com, 30 Jan 2006. Web. 21 Mar 2013.
- Gilman, A.G., Rall, T.W., Nies, A.S. and Taylor, P., Eds: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, McGraw-Hill, New York, 2001
- Haynes RH (1988). Biological context of DNA repair. In: Friedberg EC & Hanawalt PC editors, Mechanisms and Consequences of DNA Damage Processing, John Wiley & Sons Canada, Limited, 1988 pp. 577-584. ISBN 0471502693, 9780471502692
- Bernstein C, Bernstein H, Payne CM, Garewal H. (2002). DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 511(2):145-178. Review. PMID: 12052432
- Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM. (1997). Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2" Proc Natl Acad Sci U S A 94(7) 3122-3127. doi:10.1073/pnas.94.7.3122 PMID 9096356
- Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM. (2006). Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6" Carcinogenesis 27(12) 2402-2408. doi:10.1093/carcin/bgl079 PMID 16728433
- Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A. (2002). Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation" EMBO Rep 3(3) 255-260. doi:10.1093/embo-reports/kvf037 PMID 11850397
- Sedelnikova OA, Redon CE, Dickey JS, Nakamura AJ, Georgakilas AG, Bonner WM. (2010). Role of oxidatively induced DNA lesions in human pathogenesis. Mutat Res 704(1-3):152-159. doi: 10.1016/j.mrrev.2009.12.005. Review. PMID: 20060490
- Ames BN, Shigenaga MK, Hagen TM. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A. 90(17):7915-7922. Review. PMID 8367443
- Sakai A, Nakanishi M, Yoshiyama K, Maki H. (2006). Impact of reactive oxygen species on spontaneous mutagenesis in Escherichia coli. Genes Cells 11(7):767-778. PMID: 16824196
- Massie HR, Samis HV, Baird MB. (1972). The kinetics of degradation of DNA and RNA by H2O2. Biochim Biophys Acta 272(4):539-548. PMID: 5065779
- Vilenchik MM, Knudson AG. (2003) Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A 100(22) 12871-12876. PMID 14566050
- Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 1604565810 ISBN 978-1604565812
- Harris Bernstein, Carol Bernstein and Richard E. Michod (2011). Meiosis as an Evolutionary Adaptation for DNA Repair. Chapter 19 in DNA Repair. Inna Kruman editor. InTech Open Publisher. DOI: 10.5772/25117 http://www.intechopen.com/books/dna-repair/meiosis-as-an-evolutionary-adaptation-for-dna-repair