autophagy and starvation

Autophagy occurs when cells need to degrade their constituents. This occurs in most normal cells to prevent the accumulation of protein aggregates and defective cellular substructures. During starvation, high temperature, low oxygen, hormonal stimulation or intracellular stress (damaged organelles, accumulation of mutant proteins, microbial invasion) there is activation of signalling pathways that increase autophagy.
The enzyme TOR kinase is a sensor of nutrient status and a major regulator of cell growth; negatively regulating autophagy acting through autophagy-execution proteins. Various signalling pathways, such as those involved in the control of cell growth, DNA-damage repair, programmed cell death (apoptosis) and immunity also induce autophagy. .
After the cell receives the appropriate signal, the autophagy-execution proteins trigger a cascade of reactions leading to membrane rearrangements forming a double-membrane-bound vesicle called an autophagosome. An isolation membrane forms, which surrounds the cytoplasmic contents to be degraded, creating a sac the autophagosome. This vesicle then fuses with a lysosome (or a vacuole in yeast), with the release of lysosomal digestive enzymes into the lumen of the resulting autolysosome. The sequestered cytoplasmic contents are degraded inside the autolysosome into free nucleotides, amino acids and fatty acids, which are reused by the cell to maintain macro-molecular synthesis and to fuel energy production. The nutrient recycling and housekeeping functions of autophagy allows cell survival, although in certain circumstances autophagy may promote cell death
Autophagy may also stop routine protein synthesis to allow the synthesis of essential proteins when external nutrients are limited. During starvation, autophagy comes into play to ensure that the cell has sufficient amino acids to synthesize the proteins that are essential for its survival . However the synthesis of specific stress-response proteins, including autophagy-execution proteins are turned on. A coordinated strategy. and autophagy is activated.
The autophagy-specific genes are encode proteins that are components of kinase complexes, which regulate the activity of proteins and lipids through the addition of a phosphate group. Alternatively, they encode components of protein-conjugation systems, which attach to each other or to membrane lipids to form the membrane of the autophagosome.
Autophagy and apoptosis are usually been classified as different forms of programmed cell death. Whereas apoptosis invariably leads to cell death, autophagy (despite its frequent occurrence in dying cells) commonly contributes to cell survival. There is a complex, and not fully understood, relationship between autophagy and apoptosis that may vary depending on the biological context. The two pathways are regulated by common factors; they share common components; they can exert overlapping functions; and one pathway may regulate and modify the activity of the other.
Autophagy and apoptosis may occur in the same cell, both when autophagy is trying to keep cells alive and when it contributes to cell death. In some circumstances, e.g. starvation and treatment with certain DNA-damaging agents, autophagy delays the onset of apoptosis.
Review in Nature Levine Nature 2007, vol 446, 745-7

Martin Eastwood
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