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Cell damage (also known as cell injury) is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive and where possible,
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
is restored. Cell death occurs when the severity of the injury exceeds the cell's ability to repair itself. Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. Cell death may occur by
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...
or
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
.


Causes

* Physical agents such as heat or
radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...
can damage a cell by literally cooking or coagulating their contents. * Impaired nutrient supply, such as lack of oxygen or
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
, or impaired production of
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms ...
(ATP) may deprive the cell of essential materials needed to survive. *Metabolic: Hypoxia and
Ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...
*Chemical Agents *Microbial Agents:
Virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...
&
Bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
*Immunologic Agents:
Allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
and autoimmune diseases such as
Parkinson's Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
. *Genetic factors: Such as Down's syndrome and sickle cell anemia


Targets

The most notable components of the cell that are targets of cell damage are the DNA and the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. *
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
: In human cells, both normal
metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
activities and environmental factors such as
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
light and other radiations can cause DNA damage, resulting in as many as one
million One million (1,000,000), or one thousand thousand, is the natural number following 999,999 and preceding 1,000,001. The word is derived from the early Italian ''millione'' (''milione'' in modern Italian), from ''mille'', "thousand", plus the a ...
individual molecular lesions per cell per day.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 *Membrane damage: Damage to the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
disturbs the state of cell electrolytes, e.g.
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
, which when constantly increased, induces
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
. *
Mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
damage: May occur due to ATP decrease or change in
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
permeability. *
Ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to fo ...
damage: Damage to ribosomal and cellular proteins such as protein misfolding, leading to apoptotic enzyme activation.


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.


Reversible


Cellular swelling

Cellular swelling (or cloudy 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 Turgor pressure is the force within the cell that pushes the plasma membrane against the cell wall. It is also called ''hydrostatic pressure'', and is defined as the pressure in a fluid measured at a certain point within itself when at equilibri ...
, 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 The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
. This pattern of non-lethal injury is sometimes called hydropic change or vacuolar degeneration. Hydropic degeneration is a severe form of cloudy swelling. It occurs with hypokalemia due to vomiting or diarrhea. The ultrastructural changes of reversible cell injury include: * Blebbing * Blunting *distortion of
microvilli Microvilli (singular: microvillus) are microscopic cellular membrane protrusions that increase the surface area for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, ...
*loosening of intercellular attachments *mitochondrial changes *dilation of the endoplasmic reticulum


Fatty change

In fatty change, the cell has been damaged and is unable to adequately metabolize fat. Small vacuoles of fat accumulate and become dispersed within cytoplasm. Mild fatty change may have no effect on cell function; however, more severe fatty change can impair cellular function. In the liver, the enlargement of hepatocytes due to fatty change may compress adjacent
bile canaliculi Bile canaliculus (plural:bile canaliculi; also called bile capillaries) is a thin tube that collects bile secreted by hepatocytes. The bile canaliculi empty into a series of progressively larger bile ductules and ducts, which eventually become comm ...
, leading to cholestasis. Depending on the cause and severity of the lipid accumulation, fatty change is generally reversible. Fatty change is also known as fatty degeneration, fatty metamorphosis, or fatty steatosis.


Irreversible


Necrosis

Necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...
is characterised by cytoplasmic swelling, irreversible damage to the plasma membrane, and organelle breakdown leading to cell death. The stages of cellular necrosis include ''pyknosis''; clumping of chromosomes and shrinking of the nucleus of the cell'', karyorrhexis''; fragmentation of the nucleus and break up of the chromatin into unstructured granules, and ''karyolysis''; dissolution of the cell nucleus. Cytosolic components that leak through the damaged plasma membrane into the extracellular space can incur an inflammatory response. There are six types of necrosis: * Coagulative necrosis * Liquefactive necrosis * Caseous necrosis * Fat necrosis * Fibroid necrosis * Gangrenous necrosis


Apoptosis

Apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
is the programmed cell death of superfluous or potentially harmful cells in the body. It is an energy-dependent process mediated by proteolytic enzymes called caspases, which trigger cell death through the cleaving of specific proteins in the cytoplasm and nucleus. The dying cells shrink and condense into apoptotic bodies. The cell surface is altered so as to display properties that lead to rapid phagocytosis by macrophages or neighbouring cells. Unlike necrotic cell death, Neighbouring cells are not damaged by apoptosis as cytosolic products are safely isolated by membranes prior to undergoing phagocytosis. It is considered an important component of various bioprocesses including cell turnover, hormone-dependent atrophy, proper development and functioning of the immune and embryonic system, it also helps in chemical-induced cell death which is genetically mediated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade. It is also becoming clear that
mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors. There are research being conducted to focus on the
elucidation The ''Elucidation'' is an anonymous Old French poem of the early 13th century, which was written to serve as a prologue to Chrétien de Troyes' '' Perceval, le Conte du Graal''.Lacy, "Introduction." The poem counts 484 lines and cites one Master B ...
and analysis of the cell cycle machinery and signaling pathways that controls cell cycle arrest and apoptosis. 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.


Repair

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 motto of the repair process is to fill a gap caused by the damaged cells to regain structural continuity. Normal cells try to regenerate the damaged cells but this cannot always happen.


Regeneration

Regeneration of
parenchyma Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word � ...
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.


Replacement

When a cell cannot be regenerated, the body will replace it with stromal connective tissue to maintain tissue or 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.


Biochemical changes in cellular injury

ATP (adenosine triphosphate) depletion is a common biological alteration that occurs with cellular injury. This change can happen despite the inciting agent of the cell damage. A reduction in intracellular ATP can have a number of functional and morphologic consequences during cell injury. These effects include: *Failure of the ATP-dependent pumps ( pump and pump), resulting in a net influx of and ions and osmotic swelling. *ATP-depleted cells begin to undertake anaerobic metabolism to derive energy from
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of ...
which is known as
glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Mechanism T ...
. *A consequent decrease in the intracellular pH of the cell arises, which mediates harmful enzymatic processes. *Early clumping of nuclear chromatin then occurs, known as pyknosis, and leads to eventual cell death.


DNA damage and repair


DNA damage

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 DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
). 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
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to crea ...
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 recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al 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 DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
) 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.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. Nova Science Publishers is an academic publisher of books, encyclopedias, handbooks, e-books and journals, based in Hauppauge, New York. It was founded in 1985. A prolific publisher of books, Nova has received criticism from librarians for not a ...
, New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247
). In addition, an increased incidence of DNA damage and/or reduced DNA repair cause an increased risk of cancer (see
Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
Carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
and
Neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
) 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.


See also

* Cellular adaptation


References

{{pathology Cell biology Cellular senescence