Autophagy
[4][5] Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells.
[8][9][10] In macroautophagy (the most thoroughly researched form of autophagy), cytoplasmic components (like mitochondria) are targeted and isolated from the rest of the cell within a double-membrane vesicle known as an autophagosome,[11][12] 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.
[13] In its present usage, the term autophagy was coined by Belgian biochemist Christian de Duve in 1963 based on his discovery of the functions of lysosome.
[20] 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.
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.
[26][27] Initially, the genes discovered by these and other yeast groups were given different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD).
Knowledge of ATG genes provided scientists more convenient tools to dissect functions of autophagy in human health and disease.
[32] 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 homocysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells.
[41] 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.
[34][42] The autophagosome then travels through the cytoplasm of the cell to a lysosome in mammals, or vacuoles in yeast and plants,[43] and the two organelles fuse.
In fungal cells on the other hand microplipophagy constitutes the main pathway and is especially well studied in the budding yeast Saccharomyces cerevisiae.
[52] To give specific examples, the UKL1 enzyme (kinase complex) induces autophagosome biogenesis, and ATG13 (Autophagy-related protein 13) is required for phagosome formation.
[57] 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.
[77] This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.
Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of interferon and other antiviral cytokines.
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.
[92] 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.
[citation needed] Mammalian fetal oocytes face several challenges to survival throughout the stages of meiotic prophase I prior to primordial follicle assembly.
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.
[97] Another study demonstrated that skeletal muscle fibers of collagen VI in knockout mice showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive cell death.
[30] 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.
[citation needed] Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of tumor cells.
[110] Autophagy has been shown to enable continued growth of tumor cells by maintaining cellular energy production.
[116] Cells of vertebrate organisms normally activate inflammation to enhance the capacity of the immune system to clear infections and to initiate the processes that restore tissue structure and function.
[117] Therefore, it is critical to couple regulation of mechanisms for removal of cellular and bacterial debris to the principal factors that regulate inflammation: The degradation of cellular components by the lysosome during autophagy serves to recycle vital molecules and generate a pool of building blocks to help the cell respond to a changing microenvironment.
[citation needed] Excessive activity of the crinophagy form of autophagy in the insulin-producing beta cells of the pancreas could reduce the quantity of insulin available for secretion, leading to type 2 diabetes.
