Autophagy

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Revision as of 12:53, 27 February 2013 by RRM (talk | contribs) (Functions)

Autophagy is a catabolic adaptive survival response. Autophagy is the decomposition and recycling of redundant or dysfunctional cellular components by the lysosome. This ensures cellular survival during starvation by maintaining cellular energy levels and other 'nutrients' (for construction). Targeted components are isolated and transported by autophagosomes or vacuoles, which then fuse with the lysosome.

Lysosomes

Like the body, each cell contains specialised organs, called organelles. Lysosomes resemble the digestive system. Lysosomes (pH 4.8) contain weak bases with lipophilic properties and hydrolase enzymes (such as acid sphingomyelinase) that break down waste materials and cellular debris. The membrane keeps the enzymes inside. Autophagic vacuoles (trucks carrying waste) fuse with the lysosomes, which dispense their digestive enzymes into the vacuoles. Alternatively, material may cross the lysosomal barrier by the mediation of a chaperone complex (extremely selective, due to a membrane-bound protein receptor recognition system). Material from the cytoplasma may also directly engulf (by inward folding of the lysosomal membrane) into the lysosome (microautophagy). Lysosomes may process / digest remainders of dying cells or dysfunctional organelles, invading microbes / bacteria and cell surface receptor proteins. Lysosomes may also serve as a patch for when the plasma membrane is damaged, 'sealing' the wound. Lysosomes also produce proteins.

Functions

Autophagy helps to preserve organelles [1] and to keep cells functioning, as cells require a constant supply of nutrients (supplied by autophagy). [2] Energetic needs during starvation and stress are partly met by elevated autophagy. Stimulation of autophagy may also help cells to eliminate pathogens (virusses[3], bacteria etc). Failure of autophagy is thought to be one of the main reasons for the accumulation of cell damage and aging. [4] Autophagy protects against diseases such as cancer [5] [6], neurodegenerative disorders [7] [8], bacterial [9] [10] and viral [11] infections, ageing [12] [13], inflammatory diseases [14] [15] and insulin resistance [16] [17]. (supported by animal studies Full Free Article) Exercise may prevent chronic and inflammatory disease.[18] Full Free Article

Caloric restriction

Dietary derived energy and autophagy are complementary regarding normal cell energy use. Autophagy is increased in response to nutrient depletion. Autophagy is shut off during nutrient abundance. [19] Nutrient depletion evokes autophagy [20]; the degradation of membrane lipids and proteins generates free fatty acids and amino acids reused to fuel mitochondrial ATP energy production and maintain protein synthesis. [21] Unicellular organisms lacking autophagy genes (viable in normal growth conditions) die rapidly during starvation.[22] [23] Dietary restriction prolonges lifespan, but not when autophagy is inhibited. [24] Full Free Article

Exercise

Both nutrient depletion and exercise induce autophagy, and they both due so through sensing (by AMP-activated protein kinase (AMPK)) the cellular ratio of AMP to ATP.[25] Full Free Article In return, cellular autophagy function is partially required for normal levels of exercise-induced muscle AMPK activation.[26] Exercise increases autophagy (also in the absence of nutrient depletion), particularly evoking the conversion of protein for energy.[27] Full Free Article During strenuous exercise, mammals undergo metabolic changes to increase skeletal muscle glucose uptake/utilization efficiency, including increased insulin sensitivity and redistribution of glucose transporters, such as GLUT4 (also known as SLC2A4), to the plasma membrane [28] [29] which is essential for exercise-stimulated glucose uptake [30], and which are impaired when autophagy is defective.[31] Full Free Article

Autophagy is essential in skeletal muscle homeostasis, preventing accumulation of damaged mitochondria, excessive apoptosis [32] and damaged collagen fibres [33] Full Free Article, which is reversed by autophagy induced by maintenance on a low protein diet (autophagy is involved in protein quality control[34], recycling amino acids[35]) or longer starvation periods. Full Free Article Physical exercise promotes mitochondrial biogenesis, improves mitochondrial function and prevents muscle fibril degeneration by triggering autophagy.[36]

Apoptosis

The autophagy- and apotosis pathways are intertwined; Signals that activate apoptosis may also induce autophagy, and signals that inhibit apoptosis may also inhibit autophagy.[37] Free Full Text As autophagy is the recycling of (often reactive) cell material, it may be involved in apoptosis (clearing dead cells[38]), or prevent it. [39] And sometimes dying cells still use autophagy [40] Either too little (exposing cells to metabolic stress) or excessive autophagy (digesting healthy cell structures) can cause cell death, but in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. [41] At any point in the process, the autophagy is reversed by growth factors or nutrients. [42] Autophagy genes prevent the onset of apoptosis during nutrient deprivation. [43] Full Free Article