Autophagy

Autophagy is derived from Greek roots: auto, meaning 'self', and phagy, 'to eat'. This pathway is not directly a death pathway, like apoptosis, but rather a self-cannibalisation pathway. Utilizing lysosomal degradation, autophagy is responsible for cleaning the cell of unwanted proteins and degrades even complete cellular organelles. The purpose of autophagy is to maintain the homeostasis of the cell. Superfluous cell components, or even harmfully dysfunctional actors in the cells machinery are removed. Autophagy thereby acts as a maintenance apparatus that is designed to keep the cell functioning properly by removing, or rather recycling "waste".

Types of degradation

Three different types of autophagy are know which are designed to address different problems, i.e. the removal of different types of waste.

• Pexophagy, autophagy selective for degradation of peroxisomes
• Mitophagy, autophagy selective for degradation of mitochondria
• Xenophagy, autophagy selective for degradation of intracellular bacteria and viruses

Consequently autophagy is a recycling pathway that helps maintaining cellular homeostasis.

Even though autophagy has been known for over 40 years, the molecular machinery behind this process has been largely unknown until recently. Today over ~30 autophagy-related genes (ATG-genes) are known.

Autophagic processes

The cell has different ways of going about solving the problem of waste removal. Three types or processes for autophagy are knnow today.

• Microautophagy happens when lysosomes directly engulf cytoplasm
• Macroautophagy involves formation of a double-membrane structure called the autophagosome which delivers cytosolic material into the lysosome for degradation
• Chaperone-mediated autophagy (CMA) is characterized by its selectivity regarding the specific substrates (cytosolic proteins) degraded. Only proteins that have a consensus peptide sequence get recognized and degraded. In the process the substrates for degradation are transferred into the lysosome one-by-one. This process does only degrade proteins not entire organelles

Autophagy is part of everyday normal cell growth and development and is essential in helping to maintain the balance between the increase and decrease in the number of a cell content.

Purposes for autophagy

To date three main purposes or triggering events have been identified for autophagy:

• Nutrient starvation: decreased levels of amino acids can induce the autophagic processes
• Infection: autophagy plays a role in the destruction of some bacteria within the cell, and in detection of virus via pathways of the innate immune system
• Housekeeping processes: proteins and organelles are recycled

Molecular induction of autophagy

Autophagy can be induced by both internal and external stimuli. The nutrient sensor mTOR has an inhibitory effect on autophagy, under starvation conditions, mTOR is inactivated ? leading to the inhibition of autophagy being released. Hence nutrient depletion triggers autophagy. As mentioned previously, more than 30 genes have already been indicated in the actions of the mTOR signalling pathway, hence the molecular processes leading to autophagy are delicately balanced between a multitude of molecular players.

Role in disease

In principle autophagy assists in protecting the organism against pathologies, for example cancer, neurodegeneration, bacterial and viral infections, aging and heart disease. Malfunction of autophagy may therefore contribute to the development of a disease.

Disease	Activation of autophagy	Inactivation of autophagy
CANCER
Early stages	Blocks tumor growth	Favors tumor growth Renders cells unable to enter autophagic cell death after anticancer treatments
Late stages	Favors survival of cells in low-vascularized tumors Favors removal of damaged intracellular macromolecules after anticancer treatment	Prevents survival of cells in low-vascular tumors Increases efficiency of anticancer treatments; damaged macromolecules cannot be eliminated
Vascular myopathies	Promotes elimination of the cytosolic autophagic vacuoles and protein aggregate	Results in the accumulation of autophagic vacuoles that weaken skeletal and cardiac muscles
	Results in muscle waste if hyperactivated
NEURODEGENERATION
Early stages	Favors removal of cytosolic protein aggregates	Increases accumulation of cytosolic protein aggregates
Late stages	Destroys damaged neurons irreversibly by cell death	Results in accumulation of autophagic vacuoles that alter vesicular traffic
Axonal injury	Favors removal of neurotransmitter versicles and damaged organelles	Prevents removal of damaged organelles and neurotransmitter vesicles
		Cytosolic release of neurotransmitters induces apoptosis
	Provides energy and membranes for regeneration	Slows down regeneration
Infectious disease	Contributes to the elimination of bacterial and viral particles	Offers a survival environment for the bacteria that are able to inhibit autophagosome maturation Facilitates viral infection

Occurences favoring disease in italic font

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