Autophagy (or autophagocytosis) (from the Ancient Greek αὐτόφαγος autóphagos, meaning "self-devouring" and κύτος kýtos, meaning "hollow") is the natural, regulated mechanism of the cell that disassembles unnecessary or dysfunctional components. It allows the orderly degradation and recycling of cellular components.
Three forms of autophagy are commonly described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). In macroautophagy, expendable cytoplasmic constituents are targeted and isolated from the rest of the cell within a double-membraned vesicle known as an autophagosome, which, in time, fuses with an available lysosome, bringing its specialty process of waste management and disposal; and eventually the contents of the vesicle (now called an autolysosome) are degraded and recycled.
In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases it appears to promote cell death and morbidity. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels.
The name "autophagy" was coined by Belgian biochemist Christian de Duve in 1963 based on his discovery of the functions of lysosome. The identification of autophagy-related genes in yeast in the 1990s allowed researchers to deduce the mechanisms of autophagy, which eventually led to the award of the 2016 Nobel Prize in Physiology or Medicine to Japanese researcher Yoshinori Ohsumi.
Autophagy was first observed by Keith R. Porter and his student Thomas Ashford at the Rockefeller Institute. In January 1962 they reported an increased number of lysosomes in rat liver cells after the addition of glucagon, and that some displaced lysosomes towards the centre of the cell contained other cell organelles such as mitochondria. They called this autolysis after Christian de Duve and Alex B. Novikoff. However Porter and Ashford wrongly interpreted their data as lysosome formation (ignoring the pre-existing organelles). Lysosomes could not be cell organelles, but part of cytoplasm such as mitochondria, and that hydrolytic enzymes were produced by microbodies. In 1963 Hruban, Spargo and colleagues published a detailed ultrastructural description of "focal cytoplasmic degradation," which referenced a 1955 German study of injury-induced sequestration. Hruban, Spargo and colleagues recognized three continuous stages of maturation of the sequestered cytoplasm to lysosomes, and that the process was not limited to injury states that functioned under physiological conditions for "reutilization of cellular materials," and the "disposal of organelles" during differentiation. Inspired by this discovery, de Duve christened the phenomena "autophagy". Unlike Porter and Ashford, de Duve conceived the term as a part of lysosomal function while describing the role of glucagon as a major inducer of cell degradation in the liver. With his student Russell Deter, he established that lysosomes are responsible for glucagon-induced autophagy. This was the first time the fact that lysosomes are the sites of intracellular autophagy was established.
In the 1990s several groups of scientists independently discovered autophagy-related genes using the budding yeast. Notably, Yoshinori Ohsumi and Michael Thumm examined starvation-induced non-selective autophagy; in the meantime, Daniel J Klionsky discovered the cytoplasm-to-vacuole targeting (CVT) pathway, which is a form of selective autophagy. They soon found that they were in fact looking at essentially the same pathway, just from different angles. Initially, the genes discovered by these and other yeast groups were given different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD). A unified nomenclature was advocated in 2003 by the yeast researchers to use ATG to denote autophagy genes. The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi, although some have pointed out that the award could have been more inclusive.
The field of autophagy research experienced accelerated growth at the turn of the 21st century. Knowledge of ATG genes provided scientists more convenient tools to dissect functions of autophagy in human health and disease. In 1999, a landmark discovery connecting autophagy with cancer was published by Beth Levine's group. To this date, relationship between cancer and autophagy continues to be a main theme of autophagy research. The roles of autophagy in neurodegeneration and immune defense also received considerable attention. In 2003, the first Gordon Research Conference on autophagy was held at Waterville. In 2005, Daniel J Klionsky launched Autophagy, a scientific journal dedicated to this field. The first Keystone Symposia Conference on autophagy was held in 2007 at Monterey. In 2008, Carol A Mercer created a BHMT fusion protein (GST-BHMT), which showed starvation-induced site-specific fragmentation in cell lines. The degradation of betaine homo-cysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells.
In contemporary literature, the brazilian writer Leonid Bózio expresses autophagy as an existential question. The psychological drama of the book Tempos Sombrios  recounts characters consuming their own lives in an inauthentic existence.
There are three main types of autophagy, namely macroautophagy, microautophagy and Chaperone mediated autophagy. They are mediated by the autophagy-related genes and their associated enzymes. Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy, lipophagy, pexophagy, chlorophagy, ribophagy and others.
Macroautophagy is the main pathway, used primarily to eradicate damaged cell organelles or unused proteins. First the phagophore engulfs the material that needs to be degraded, which forms a double membrane known as an autophagosome, around the organelle marked for destruction. The autophagosome then travels through the cytoplasm of the cell to a lysosome, and the two organelles fuse. Within the lysosome, the contents of the autophagosome are degraded via acidic lysosomal hydrolase.
Microautophagy, on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome. This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.
Chaperone-mediated autophagy, or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex. This means that a protein must contain the recognition site for this hsc70 complex which will allow it to bind to this chaperone, forming the CMA- substrate/chaperone complex. This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA receptor, allowing it to enter the cell. Upon recognition, the substrate protein gets unfolded and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone. CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.
Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by Atg32 (in yeast) and NIX and its regulator BNIP3 in mammals. Mitophagy is regulated by PINK1 and parkin proteins. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.
Lipophagy is the degradation of lipids by autophagy, a function which has been shown to exist in both animal and fungal cells. The role of lipophagy in plant cells, however, remains elusive. In lipophagy the target are lipid structures called lipid droplets (LDs), spheric "organelles" with a core of mainly triacylglycerols (TAGs) and a unilayer of phospholipids and membrane proteins. In animal cells the main lipophagic pathway is via the engulfment of LDs by the phagophore, macroautophagy. In fungal cells on the other hand microplipophagy constitutes the main pathway and is especially well studied in the budding yeast Saccharomyces cerevisiae. Lipophagy was first discovered in mice and published 2009.
Autophagy is executed by autophagy-related (Atg) genes. Prior to 2003, ten or more names were used, but after this point a unified nomenclature was devised by fungal autophagy researchers. Atg or ATG stands for autophagy related. It does not specify gene or a protein.
The first autophagy genes were identified by genetic screens conducted in Saccharomyces cerevisiae. Following their identification those genes were functionally characterized and their orthologs in a variety of different organisms were identified and studied.
In mammals, amino acid sensing and additional signals such as growth factors and reactive oxygen species regulate the activity of the protein kinases mTOR and AMPK. These two kinases regulate autophagy through inhibitory phosphorylation of the Unc-51-like kinases ULK1 and ULK2 (mammalian homologues of Atg1). Induction of autophagy results in the dephosphorylation and activation of the ULK kinases. ULK is part of a protein complex containing Atg13, Atg101 and FIP200. ULK phosphorylates and activates Beclin-1 (mammalian homologue of Atg6), which is also part of a protein complex. The autophagy-inducible Beclin-1 complex contains the proteins p150, Atg14L and the class III phosphatidylinositol 3-phosphate kinase (PI(3)K) Vps34. The active ULK and Beclin-1 complexes re-localize to the site of autophagosome initiation, the phagophore, where they both contribute to the activation of downstream autophagy components.
Once active, VPS34 phosphorylates the lipid phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns(3)P) on the surface of the phagophore. The generated PtdIns(3)P is used as a docking point for proteins harboring a PtdIns(3)P binding motif. WIPI2, a PtdIns(3)P binding protein of the WIPI (WD-repeat protein interacting with phosphoinositides) protein family, was recently shown to physically bind Atg16L1. Atg16L1 is a member of an E3-like protein complex involved in one of two ubiquitin-like conjugation systems essential for autophagosome formation. Its binding by WIPI2 recruits it to the phagophore and mediates its activity.
The first of the two ubiquitin-like conjugation systems involved in autophagy covalently binds the ubiquitin-like protein Atg12 to Atg5. The resulting conjugate protein then binds Atg16L1 to form an E3-like complex which functions as part of the second ubiquitin-like conjugation system. This complex binds and activates Atg3, which covalently attaches mammalian homologues of the ubiquitin-like yeast protein ATG8 (LC3A-C, GATE16, and GABARAPL1-3), the most studied being LC3 proteins, to the lipid phosphatidylethanolamine (PE) on the surface of autophagosomes. Lipidated LC3 contributes to the closure of autophagosomes, and enables the docking of specific cargos and adaptor proteins such as Sequestosome-1/p62. The completed autophagosome then fuses with a lysosome through the actions of multiple proteins, including SNAREs and UVRAG. Following the fusion LC3 is retained on the vesicle's inner side and degraded along with the cargo, while the LC3 molecules attached to the outer side are cleaved off by Atg4 and recycled. The contents of the autolysosome are subsequently degraded and their building blocks are released from the vesicle through the action of permeases.
Autophagy has roles in various cellular functions. One particular example is in yeasts, where the nutrient starvation induces a high level of autophagy. This allows unneeded proteins to be degraded and the amino acids recycled for the synthesis of proteins that are essential for survival. In higher eukaryotes, autophagy is induced in response to the nutrient depletion that occurs in animals at birth after severing off the trans-placental food supply, as well as that of nutrient starved cultured cells and tissues. Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions. Studies on the apg mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved in autophagy in yeast. A gene known as ATG7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in atg7-deficient mice.
In microbiology, xenophagy is the autophagic degradation of infectious particles. Cellular autophagic machinery also play an important role in innate immunity. Intracellular pathogens, such as Mycobacterium tuberculosis (the bacterium which is responsible for tuberculosis) are targeted for degradation by the same cellular machinery and regulatory mechanisms that target host mitochondria for degradation. Incidentally, this is further evidence for the endosymbiotic hypothesis. This process generally leads to the destruction of the invasive microorganism, although some bacteria can block the maturation of phagosomes into degradative organelles called phagolysosomes. Stimulation of autophagy in infected cells can help overcome this phenomenon, restoring pathogen degradation.
Vesicular stomatitis virus is believed to be taken up by the autophagosome from the cytosol and translocated to the endosomes where detection takes place by a pattern recognition receptor called toll-like receptor 7, detecting single stranded RNA. Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of interferon and other antiviral cytokines. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication. Galectin-8 has recently been identified as an intracellular "danger receptor", able to initiate autophagy against intracellular pathogens. When galectin-8 binds to a damaged vacuole, it recruits an autophagy adaptor such as NDP52 leading to the formation of an autophagosome and bacterial degradation.
Autophagy degrades damaged organelles, cell membranes and proteins, and electing against autophagy is thought to be one of the main reasons for the accumulation of damaged cells and aging. Autophagy and autophagy regulators are involved in response to lysosomal damage, often directed by galectins such as galectin-3 and galectin-8, which in turn recruit receptors such as TRIM16. and NDP52 plus directly affect mTOR and AMPK activity, whereas mTOR and AMPK inhibit and activate autophagy, respectively
One of the mechanisms of programmed cell death (PCD) is associated with the appearance of autophagosomes and depends on autophagy proteins. This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies so far did not prove a causative relationship between the autophagic process and cell death. In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival mechanism. Studies of the metamorphosis of insects have shown cells undergoing a form of PCD that appears distinct from other forms; these have been proposed as examples of autophagic cell death. Recent pharmacological and biochemical studies have proposed that survival and lethal autophagy can be distinguished by the type and degree of regulatory signaling during stress particularly after viral infection. Although promising, these findings have not been examined in non-viral systems.
Autophagy is essential for basal homeostasis; it is also extremely important in maintaining muscle homeostasis during physical exercise. Autophagy at the molecular level is only partially understood. A study of mice shows that autophagy is important for the ever-changing demands of their nutritional and energy needs, particularly through the metabolic pathways of protein catabolism. In a 2012 study conducted by the University of Texas Southwestern Medical Center in Dallas, mutant mice (with a knock-in mutation of BCL2 phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were deficient in stress-induced autophagy) were tested to challenge this theory. Results showed that when compared to a control group, these mice illustrated a decrease in endurance and an altered glucose metabolism during acute exercise.
Another study demonstrated that skeletal muscle fibres of collagen VI knockout mice showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive cell death. Exercise-induced autophagy was unsuccessful however; but when autophagy was induced artificially post-exercise, the accumulation of damaged organelles in collagen VI deficient muscle fibres was prevented and cellular homeostasis was maintained. Both studies demonstrate that autophagy induction may contribute to the beneficial metabolic effects of exercise and that it is essential in the maintaining of muscle homeostasis during exercise, particularly in collagen VI fibres.
Work at the Institute for Cell Biology, University of Bonn, showed that a certain type of autophagy, i.e. chaperone-assisted selective autophagy (CASA), is induced in contracting muscles and is required for maintaining the muscle sarcomere under mechanical tension. The CASA chaperone complex recognizes mechanically damaged cytoskeleton components and directs these components through a ubiquitin-dependent autophagic sorting pathway to lysosomes for disposal. This is necessary for maintaining muscle activity.
Because autophagy decreases with age and age is a major risk factor for osteoarthritis, the role of autophagy in the development of this disease is suggested. Proteins involved in autophagy are reduced with age in both human and mouse articular cartilage. Mechanical injury to cartilage explants in culture also reduced autophagy proteins. Autophagy is constantly activated in normal cartilage but it is compromised with age and precedes cartilage cell death and structural damage. Thus autophagy is involved in a normal protective process (chondroprotection) in the joint.
Cancer often occurs when several different pathways that regulate cell differentiation are disturbed. Autophagy plays an important role in cancer – both in protecting against cancer as well as potentially contributing to the growth of cancer. Autophagy can contribute to cancer by promoting survival of tumor cells that have been starved, or that degrade apoptotic mediators through autophagy: in such cases, use of inhibitors of the late stages of autophagy (such as chloroquine), on the cells that use autophagy to survive, increases the number of cancer cells killed by antineoplastic drugs.
The role of autophagy in cancer is one that has been highly researched and reviewed. There is evidence that emphasizes the role of autophagy both as a tumor suppressor as well as a factor in tumor cell survival. However, recent research has been able to show that autophagy is more likely to be used as a tumor suppressor according to several models.
Several experiments have been done with mice and varying Beclin1, a protein that regulates autophagy. When the Beclin1 gene was altered to be heterozygous (Beclin 1+/-), the mice were found to be tumor prone. However, when Beclin1 was overexpressed, tumor development was inhibited. Care should be exercised when interpreting phenotypes of beclin mutants and attributing the observations to a defect in autophagy, however: Beclin1 is generally required for phosphatidylinositol 3- phosphate production and as such it affects numerous lysosomal and endosomal functions, including endocytosis and endocytic degradation of activated growth factor receptors. In support of the possibility that Beclin1 affects cancer development through an autophagy-independent pathway is the fact that core autophagy factors which are not known to affect other cellular processes and are definitely not known to affect cell proliferation and cell death, such as Atg7 or Atg5, show a much different phenotype when the respective gene is knocked out, which does not include tumor formation. In addition, full knockout of Beclin1 is embryonic lethal whereas knockout of Atg7 or Atg5 is not.
Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of tumor cells.
Alternatively, autophagy has also been shown to play a large role in tumor cell survival. In cancerous cells, autophagy is used as a way to deal with stress on the cell. Induction of autophagy by miRNA-4673, for example, is a pro-survival mechanism that improves the resistance of cancer cells to radiation. Once these autophagy related genes were inhibited, cell death was potentiated. The increase in metabolic energy is offset by autophagy functions. These metabolic stresses include hypoxia, nutrient deprivation, and an increase in proliferation. These stresses activate autophagy in order to recycle ATP and maintain survival of the cancerous cells. Autophagy has been shown to enable continued growth of tumor cells by maintaining cellular energy production. By inhibiting autophagy genes in these tumors cells, regression of the tumor and extended survival of the organs affected by the tumors were found. Furthermore, inhibition of autophagy has also been shown to enhance the effectiveness of anticancer therapies.
Cells that undergo an extreme amount of stress experience cell death either through apoptosis or necrosis. Prolonged autophagy activation leads to a high turnover rate of proteins and organelles. A high rate above the survival threshold may kill cancer cells with a high apoptotic threshold. This technique can be utilized as a therapeutic cancer treatment.
New developments in research have found that targeted autophagy may be a viable therapeutic solution in fighting cancer. As discussed above, autophagy plays both a role in tumor suppression and tumor cell survival. Thus, the qualities of autophagy can be used as a strategy for cancer prevention. The first strategy is to induce autophagy and enhance its tumor suppression attributes. The second strategy is to inhibit autophagy and thus induce apoptosis.
The first strategy has been tested by looking at dose-response anti-tumor effects during autophagy-induced therapies. These therapies have shown that autophagy increases in a dose-dependent manner. This is directly related to the growth of cancer cells in a dose-dependent manner as well. This data supports the development of therapies that will encourage autophagy. Secondly, inhibiting the protein pathways directly known to induce autophagy may also serve as an anticancer therapy.
The second strategy is based on the idea that autophagy is a protein degradation system used to maintain homeostasis and the findings that inhibition of autophagy often leads to apoptosis. Inhibition of autophagy is riskier as it may lead to cell survival instead of the desired cell death.
Negative regulators of autophagy, such as mTOR, cFLIP, and EGFR are orchestrated to function within different stages of the autophagy cascade. The end-products of autophagic digestion may also serve as a negative- feedback regulatory mechanism to stop prolonged activity.
Parkinson disease is a neurodegenerative disorder partially caused by the cell death of brain and brain stem cells in many nuclei like the substantia nigra. Parkinson's disease is characterized by inclusions of a protein called alpha-synuclien (Lewy bodies) in affected neurons that cells cannot break down. Deregulation of the autophagy pathway and mutation of alleles regulating autophagy are believed to cause neurodegenerative diseases. Autophagy is essential for neuronal survival. Without efficient autophagy, neurons gather ubiquitinated protein aggregates and degrade. Ubiquitinated proteins are proteins that have been tagged with ubiquitin to get degraded. Mutations of synuclien alleles lead to lysosome pH increase and hydrolase inhibition. As a result, lysosomes degradative capacity is decreased. There are several genetic mutations implicated in the disease, including loss of function PINK1 and Parkin. Loss of function in these genes can lead to damaged mitochondrial accumulation and protein aggregates than can lead to cellular degeneration. Mitochondria is involved in Parkinson's disease. In idiopathic Parkinson's disease, the disease is commonly caused by dysfunctional mitochondria, cellular oxidative stress, autophagic alterations and the aggregation of proteins. These can lead to mitochondrial swelling and depolarization.
Since dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, great efforts are invested to identify and characterize small synthetic or natural molecules that can regulate it.
Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998).[supplied by OMIM]Autophagy requires the covalent attachment of the protein Atg12 to ATG5 through a ubiquitin-like conjugation system. The Atg12-Atg5 conjugate then promotes the conjugation of ATG8 to the lipid phosphatidylethanolamine.Atg12 was found to be involved in apoptosis. This protein promotes apoptosis through an interaction with anti-apoptotic members of the Bcl-2 family.ATG3
In molecular biology, autophagy related 3 (Atg3) is the E2 enzyme for the LC3 lipidation process. It is essential for autophagocytosis. The super protein complex, the Atg16L complex, consists of multiple Atg12-Atg5 conjugates. Atg16L has an E3-like role in the LC3 lipidation reaction. The activated intermediate, LC3-Atg3 (E2), is recruited to the site where the lipidation takes place.Atg3 catalyses the conjugation of Atg8 and phosphatidylethanolamine (PE). Atg3 has an alpha/beta-fold, and its core region is topologically similar to canonical E2 enzymes. Atg3 has two regions inserted in the core region and another with a long alpha-helical structure that protrudes from the core region as far as 30 A. It interacts with atg8 through an intermediate thioester bond between Cys-288 and the C-terminal Gly of atg8. It also interacts with the C-terminal region of the E1-like atg7 enzyme.
Autophagocytosis is a starvation-induced process responsible for transport of cytoplasmic proteins to the lysosome/vacuole. Atg3 is a ubiquitin like modifier that is topologically similar to the canonical E2 enzyme. It catalyses the conjugation of Atg8 and phosphatidylethanolamine.Atg3 consists of three domains, an N-terminal domain, a catalytic domain and a C-terminal domain. The catalytic domain contains a cysteine residue within an HPC motif, this is the putative active-site residue for recognition of the Apg5 subunit of the autophagosome complex. The small C-terminal domain is likely to be a distinct binding region for the stability of the autophagosome complex. It carries a highly characteristic conserved FLKF sequence motif.ATG7
Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.ATG 7, present in both plant and animal genomes, acts as an essential protein for cell degradation and its recycling. The sequence associates with the ubiquitin- proteasome system, UPS, required for the unique development of an autophagosomal membrane and fusion within cells.ATG7 was identified based on homology to yeast cells Pichia pastoris GSA7 and Saccharomyces cerevisiae APG7. The protein appears to be required for fusion of peroxisomal and vacuolar membranes.Autophagy is an important cellular process that helps in maintaining homeostasis. It goes through destroying and recycling the cytoplasmic organelles and macromolecules. During the initiation of autophagy, ATG7 acts like an E-1 enzyme for ubiquitin-like proteins (UBL) such as ATG12 and ATG8. ATG7 helps these UBL proteins in targeting their molecule by binding to them and activating their transfer to an E-2 enzyme. ATG7's role in both of these autophagy-specific UBL systems makes it an essential regulator of autophagosome assembly.Homologous to the ATP-binding and catalytic sites of E1 activator proteins, ATG7 uses its cysteine residue to create a thiol-ester bond with free Ubiquitin molecules. Through UPS, Ubiquitin will continue to bind to other autophagy-related proteins, E2 conjugation proteins and E3 protein ligases, to attach Ubiquitins to a target substrate to induce autophagy.ATG 7 is often associated with ATG12/ ATG5 sequenced ubiquitination cascade. As well in presence of p53 cell cycle pathways during stressed and nutrient poor environments.ATG8
Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals (see for example GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3B2, and MAP1LC3C), this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.Acute myeloblastic leukemia with maturation
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).Acute myeloid leukemia (AML) is a type of cancer affecting blood cells that eventually develop into non-lymphocyte white blood cells. The disease originates from the bone marrow, the soft inner portion of select bones where blood stem cells develop into either lymphocyte or in this particular condition, myeloid cells. This acute disease prevents bone marrow cells from properly maturing, thus causing an accumulation of immature myeloblast cells in the bone marrow.
Acute myeloid leukemia is more lethal than chronic myeloid leukemia, a disease that affects the same myeloid cells, but at a different pace. Many of the immature blast cells in acute myeloid leukemia have a higher loss of function and thus, a higher inability to carry out normal functions than those more developed immature myeloblast cells in chronic myeloid leukemia (O’Donnell et al. 2012). Acute in acute myeloid leukemia means that the amounts of blast cells are increasing at a very high rate. Myeloid refers to the type of white blood cells that are affected by the condition.
Acute myeloid leukemia is the most common acute leukemia that is affecting the adult population. The 5-year survival rate for the cancer stands at around 26% (ACS, 2016).
M2 acute myeloblastic leukemia with maturation refers to the subtype of acute myeloid leukemia characterized by the maturation stages of the myeloid cell development and the location of the AML1 gene. One of the hallmarks of M2 subtype acute myeloid leukemia is the formation of a fusion protein, AML1-ETO or RUNX1-RUNX1T1, due to a translocation of chromosome 8 to chromosome 21 or t(8;21) (Miyoshi et al., 1991, Andrieu et al., 1996). This cytogenetic abnormality has been found in 90% of M2 acute myeloblastic leukemia; while the other 10% constitutes a mix of M1 and M4 acute myeloid leukemia (GFHC, 1990).
Another translocation between chromosome 6p23 and chromosome 9q34 is also associated with the M2 subtype. The t(6;9) causes the formation of a fusion oncogene made of DEK (6p23) and CAN/NUP214 (9q34). This rare translocation has a poor prognosis compared to the t(8;21) because 70% of t(6;9) acute myeloid leukemia patients have the FLT3-ITD mutation (Schwartz et al., 1983, Kottaridis, 2001). The FLT-ITD mutation is one of the most lethal mutations in acute myeloid leukemia (Chi et al., 2008).
M2 acute myeloblastic leukemia with maturation, as classified by the FAB system, constitutes 25% of adult AML (Wiki Main article: AML).Ambroxol
Ambroxol is a drug that breaks up phlegm, used in the treatment of respiratory diseases associated with viscid or excessive mucus. Recently, a hypothesis suggested that it may have a potential role in treatment of Paget's disease of bone, Parkinsonism, and other common diseases of aging-associated diseases involving dysfunction of autophagy. Ambroxol is often administered as an active ingredient in cough syrup.
It was patented in 1966 and came into medical use in 1979.Autophagin
Autophagin-1 (Atg4/Apg4) is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy. Human Atg4 homologues cleave the carboxyl termini of the three human Atg8 homologues, microtubule-associated protein light chain 3 (LC3), GABARAP, and GATE-16.The rapid advancement in our understanding of the mechanisms and regulation of autophagy has placed this process in the center of current research in major human disorders. The future challenge is to develop easy methods to separately manipulate the activity of each of the autophagic pathways. This would allow researchers to further understand their contribution to disease such as cancer, neurodegeneration, infectious disease, muscular disorders and possibly will provide therapeutic tools.Autophagy (journal)
Autophagy is a monthly peer-reviewed scientific journal covering all aspects of cell autophagy. It is published by Taylor & Francis and the editor-in-chief is Daniel J. Klionsky (University of Michigan).Axotomy
An axotomy is the cutting or otherwise severing of an axon. Derived from axo- (=axon) and -tomy (=surgery). This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better understand nervous system diseases.Axotomy may cause neuronal cell death, especially in embryonic or neonatal animals, as this is the period in which neurons are dependent on their targets for the supply of survival factors. In mature animals, where survival factors are derived locally or via autocrine loops, axotomy of peripheral neurons and motoneurons can lead to a robust regenerative response without any neuronal death. In both cases, autophagy is observed to markedly increase. Autophagy could either clear the way for neuronal degeneration or it could be a medium for cell destruction.Bafilomycin
The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.Bafilomycin A1 specifically targets the vacuolar-type H+ -ATPase (V-ATPase) enzyme, a membrane spanning proton pump that acidifies either the extracellular environment or intracellular organelles such as the lysosome. At higher micromolar concentrations, Bafilomycin A1 also acts on P-type ATPases, which have a phosphorylated transitional state.Bafilomycin A1 serves as an important tool compound in many in vitro research applications; however, its clinical use is limited by a substantial toxicity profile.Cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.David C. Rubinsztein
David Chaim Rubinsztein (born 1963) FRS FMedSci is the Deputy Director of the Cambridge Institute of Medical Research (CIMR), the Academic Lead of the Alzheimer's Research UK (ARUK) Cambridge Drug Discovery Institute,, Professor of Molecular Neurogenetics at the University of Cambridge. and a UK Dementia Research Institute Professor.Lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins, and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, cell signaling, and energy metabolism.
Lysosomes act as the waste disposal system of the cell by digesting obsolete or un-used materials in the cytoplasm, from both inside and outside the cell. Material from outside the cell is taken-up through endocytosis, while material from the inside of the cell is digested through autophagy. The sizes of the organelles vary greatly—the larger ones can be more than 10 times the size of the smaller ones. They were discovered and named by Belgian biologist Christian de Duve, who eventually received the Nobel Prize in Physiology or Medicine in 1974.
Lysosomes are known to contain more than 60 different enzymes, and have more than 50 membrane proteins. Enzymes of the lysosomes are synthesised in the rough endoplasmic reticulum. The enzymes are imported from the Golgi apparatus in small vesicles, which fuse with larger acidic vesicles. Enzymes destined for a lysosome are specifically tagged with the molecule mannose 6-phosphate, so that they are properly sorted into acidified vesicles.Synthesis of lysosomal enzymes is controlled by nuclear genes. Mutations in the genes for these enzymes are responsible for more than 30 different human genetic disorders, which are collectively known as lysosomal storage diseases. These diseases result from an accumulation of specific substrates, due to the inability to break them down. These genetic defects are related to several neurodegenerative disorders, cancers, cardiovascular diseases, and ageing-related diseases.Lysosomes should not be confused with liposomes, or with micelles.MTOR
The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes. In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors. mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.Myopathy, X-linked, with excessive autophagy
X-linked myopathy with excessive autophagy (XMEA) is a rare childhood onset disease characterized by slow progressive vacuolation and atrophy of skeletal muscle. There is no known cardiac or intellectual involvement.Programmed cell death
Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program, and is also referred to as Cellular Suicide. PCD is carried out in a biological process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.
Apoptosis and autophagy, both are the forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.Reactive oxygen species
Reactive oxygen species (ROS) are chemically reactive chemical species containing oxygen. Examples include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
In a biological context, ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress. The production of ROS is strongly influenced by stress factor responses in plants, these factors that increase ROS production include drought, salinity, chilling, nutrient deficiency, metal toxicity and UV-B radiation. ROS are also generated by exogenous sources such as ionizing radiation.Self-cannibalism
Self-cannibalism is the practice of eating oneself, also called autocannibalism, or autosarcophagy. A similar term which is applied differently is autophagy, which specifically denotes the normal process of self-degradation by cells. While almost an exclusive term for this process, autophagy nonetheless has occasionally made its way into more common usage.Yoshinori Ohsumi
Yoshinori Ohsumi (大隅 良典, Ōsumi Yoshinori, born February 9, 1945) is a Japanese cell biologist specializing in autophagy, the process that cells use to destroy and recycle cellular components. Ohsumi is a professor at Tokyo Institute of Technology's Institute of Innovative Research. He received the Kyoto Prize for Basic Sciences in 2012, the 2016 Nobel Prize in Physiology or Medicine, and the 2017 Breakthrough Prize in Life Sciences for his discoveries of mechanisms for autophagy.