Effects of ROS on cell metabolism are well documented in a variety of species.
genes and mobilization of
ion transporters. This implicates them in control of cellular function. In particular,
platelets involved in
wound repair and
blood homeostasis release ROS to recruit additional platelets to sites of
injury. These also provide a link to the adaptive
immune system via the recruitment of
leukocytes. Reactive oxygen species are implicated in cellular activity to a variety of inflammatory responses including
cardiovascular disease. They may also be involved in
hearing impairment via
cochlear damage induced by
elevated sound levels, in
ototoxicity of drugs such as
cisplatin, and in congenital deafness in both animals and humans. ROS are also implicated in mediation of
apoptosis or programmed cell death and
ischaemic injury. Specific examples include
stroke and
heart attack. In general, the harmful effects of reactive oxygen species on the cell are the damage of DNA or RNA, oxidation of polyunsaturated fatty acids in lipids (
lipid peroxidation), oxidation of amino acids in proteins, and oxidative deactivation of specific enzymes by oxidation co-factors.
Pathogen response When a plant recognizes an attacking pathogen, one of the first induced reactions is to rapidly produce
superoxide () or
hydrogen peroxide () to strengthen the cell wall. This prevents the spread of the pathogen to other parts of the plant, essentially forming a net around the pathogen to restrict movement and reproduction. In the mammalian host, ROS is induced as an antimicrobial defense. The
uracil released by microorganism triggers the production and activity of DUOX, the ROS-producing enzyme in the intestine. DUOX activity is induced according to the level of uracil in the gut; under basal conditions, it is down-regulated by the protein kinase
MkP3. The tight regulation of DUOX avoids excessive production of ROS and facilitates differentiation between benign and damage-inducing microorganisms in the gut. The manner in which ROS defends the host from invading microbe is not fully understood. One of the more likely modes of defense is damage to microbial DNA. Studies using
Salmonella demonstrated that DNA repair mechanisms were required to resist killing by ROS. A role for ROS in antiviral defense mechanisms has been demonstrated via Rig-like helicase-1 and mitochondrial antiviral signaling protein. Increased levels of ROS potentiate signaling through this mitochondria-associated antiviral receptor to activate interferon regulatory factor (IRF)-3, IRF-7, and nuclear factor kappa B (NF-κB), resulting in an antiviral state. Respiratory epithelial cells induce mitochondrial ROS in response to influenza infection. This induction of ROS led to the induction of type III interferon and the induction of an antiviral state, limiting viral replication. In host defense against mycobacteria, ROS play a role, although direct killing is likely not the key mechanism; rather, ROS likely affect ROS-dependent signalling controls, such as cytokine production, autophagy, and granuloma formation. Reactive oxygen species are also implicated in activation,
anergy and apoptosis of
T cells.
Oxidative damage In
aerobic organisms the energy needed to fuel biological functions is produced in the
mitochondria via the
electron transport chain. Reactive oxygen species (ROS) with the potential to cause
cellular damage are produced along with the release of energy. ROS can damage lipids,
DNA,
RNA, and proteins, which, in theory, contributes to the
physiology of
aging. ROS are produced as a normal product of
cellular metabolism. In particular, one major contributor to oxidative damage is
hydrogen peroxide (H2O2), which is converted from
superoxide that leaks from the mitochondria.
Catalase and
superoxide dismutase ameliorate the damaging effects of hydrogen peroxide and superoxide, respectively, by converting these compounds into
oxygen and
hydrogen peroxide (which is later converted to water), resulting in the production of
benign molecules. However, this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects.
Cell death A cancer cell can die in three ways:
apoptosis,
necrosis, and
autophagy. Excessive ROS can induce apoptosis through both the extrinsic and intrinsic pathways. In the extrinsic pathway of apoptosis, ROS are generated by Fas ligand as an upstream event for Fas activation via phosphorylation, which is necessary for subsequent recruitment of Fas-associated protein with death domain and caspase 8 as well as apoptosis induction. In the intrinsic pathway, ROS function to facilitate cytochrome c release by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as inhibiting pore-destabilizing proteins (Bcl-2-associated X protein, Bcl-2 homologous antagonist/killer). The intrinsic pathway is also known as the caspase cascade and is induced through mitochondrial damage which triggers the release of cytochrome c. DNA damage, oxidative stress, and loss of mitochondrial membrane potential lead to the release of the pro-apoptotic proteins mentioned above stimulating apoptosis. Mitochondrial damage is closely linked to apoptosis and since mitochondria are easily targeted there is potential for cancer therapy. The cytotoxic nature of ROS is a driving force behind apoptosis, but in even higher amounts, ROS can result in both apoptosis and necrosis, a form of uncontrolled cell death, in cancer cells. Numerous studies have shown the pathways and associations between ROS levels and apoptosis, but a newer line of study has connected ROS levels and autophagy. ROS can also induce cell death through autophagy, which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted or damaged organelles and protein aggregates) for degradation in lysosomes. Therefore, autophagy can also regulate the cell's health in times of oxidative stress. Autophagy can be induced by ROS levels through many pathways in the cell in an attempt to dispose of harmful organelles and prevent damage, such as carcinogens, without inducing apoptosis. Autophagic cell death can be prompted by the over expression of autophagy where the cell digests too much of itself in an attempt to minimize the damage and can no longer survive. When this type of cell death occurs, an increase or loss of control of autophagy regulating genes is commonly co-observed. Thus, once a more in-depth understanding of autophagic cell death is attained and its relation to ROS, this form of programmed cell death may serve as a future cancer therapy. Autophagy and apoptosis are distinct mechanisms for cell death brought on by high levels of ROS. Autophagy and apoptosis, however, rarely act through strictly independent pathways. There is a clear connection between ROS and autophagy and a correlation seen between excessive amounts of ROS leading to apoptosis. On the other hand, normal cells appear to have, under lower basal stress and reserve, a higher capacity to cope with additional ROS-generating insults than cancer cells do. Therefore, the elevation of ROS in all cells can be used to achieve the selective killing of cancer cells.
James Watson and others have proposed that lack of intracellular ROS due to a lack of physical exercise may contribute to the malignant progression of cancer, because spikes of ROS are needed to correctly fold proteins in the endoplasmic reticulum and low ROS levels may thus aspecifically hamper the formation of tumor suppressor proteins. Moreover, high inducers of ROS such as 2-deoxy-D-glucose and carbohydrate-based inducers of cellular stress induce cancer cell death more potently because they exploit the cancer cell's high avidity for sugars. == See also ==