Autophagy is a cytoplasmic cellular mechanism whereby potentially toxic constituents, (e.g., misfolded proteins and dysfunctional organelles) are recognized, compartmentalized, and enzymatically degraded.
This ubiquitous, homeostatic “housekeeping” process is modulated by highly complex, multifactorial interactions resulting from external or internal stimuli. External stressors such as caloric restriction, hypoxia, or invading microbes can trigger the complex genetic responses that modulate autophagy. The internal build-up of toxic or damaged constituents can also set the cascade in motion.
The best characterized form of autophagy, macroautophagy, will be outlined briefly below; however, other intracellular recycling mechanisms outside the scope of this introduction are also a part of the overall, and perhaps interdependent processes of intracellular auto-digestion.
Figure 1 shows a highly simplified diagram outlining how targeted materials are first encased in a bilayer membrane separating them from the normal cellular environment (phagophore formation). As the phagophore elongates and nears closure, the autophagic biomarker, LC3-II, is generated and becomes associated with the surrounding membranes. This completed structure containing material to be digested is termed an autophagosome.
Autophagosomes then fuse with lysosomes containing acid hydrolases in a low pH environment. An autolysosome results wherein the lysosomal enzymes are released in a protected, acidic environment favorable to degradation. Toxic or damaged cellular constituents are thus metabolized, releasing their subunits for potential re-use by the cell.
LC3-II thus provides a potential biomarker for measuring autophagic activity in individual cells.
The progression of several diseases (see below) has been linked to alterations in autophagic functioning and it has been widely hypothesized that modulation of autophagy may reduce disease symptoms or even modify progression in diseases of aging, neurodegeneration, inflammatory diseases, and many others.
Autophagy induced by caloric restriction may explain the good health and longevity resulting from ultra-low calorie diets – perhaps resulting from a reduction of toxic intracellular particles and more efficient cellular functioning.
In addition, increased autophagic digestion of damaged mitochondria may provide a safety net from leaking reactive oxygen species (ROS) that may induce oncogenic DNA mutations and apoptosis (cell death).
These and similar observations have led to the search for autophagy-modulating drugs and ways to target them toward specific disease indications.This outcome may manifest as primary therapeutics or adjuncts to the current standard of care.
The following briefly describes representative therapeutic areas affected by autophagy:
|Disease Area||Role of Autophagy|
|Diseases of Aging||Autophagy stimulation can lead to improved overall cellular function and resistance to a variety of diseases and disorders.|
|Neurodegenerative Diseases||Autophagy may affect diseases marked by the build-up of toxic constituents in neurons/axons resulting in dystrophies and neuronal malfunction. In addition, efficient removal of damaged mitochondria can protect against ROS damage.|
|Immune Responses, Autoimmune Disease & Inflammation||Autophagy is involved in immune recognition, the regulation of T cell maturation, and overall B and T cell homeostasis. There are also effects on inflammatory cytokines that can be positive or negative in various disease states.|
|Diabetes & Metabolic Diseases||Up-regulation of autophagy improves insulin sensitivity. Autophagy also helps maintain islet structure/function, the β-cell response to fatty diets, and several other aspects of lipid metabolism.|
|Liver Disease||Autophagy plays a role in liver ischemia re-profusion injury, hepatitis B and C infection, hepatocellular carcinoma, α -1-antitrypsin deficiency, and chronic alcohol-induced cell death.|
|Infection||Autophagy eliminates certain microorganisms, regulates innate immunity, and moderates inflammatory responses to microbial invasion.|
|Cancer||Autophagy suppresses tumor growth in some cancers, especially in the early stages but can also stimulate other cancers. Drugs that inhibit autophagy may be useful in selected diseases, e.g., pancreatic cancer.|
A better understanding of autophagy as it relates specifically to the above will lead to improved methods of treating and diagnosing numerous diseases with high unmet need.
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