Autophagy

Autophagy is the digestion of damaged cellular organelles and tissue sick for later recycling or reuse. Its ancient Greek wording is derived from the words for “hollow” and “self-devouring” or “eating itself”, which accurately describes it as a natural way of pruning dysfunctional parts. Autophagy is precisely controlled and focused with the help of lysosomes (in animals) or other digestive factors that “devour” cellular components. These cellular components may take the form of organelles, protein aggregates or dysfunctional ribosomal proteins (the body’s protein producers).

Autophagy is often said to be a process of self-degradation and usually occurs in response to stress or disease. Stress usually comes from a drive to survive in times of nutritional stress or energy depletion, or even from the cellular stress of experiencing disease or initiating cell death. Autophagy can be said to play a role in cellular repair and detoxification. All of this can be precisely targeted with the help of cell surface antigens, which give autophagy a role in protecting against specific presentations of disease (i.e. cancer, diabetes, autoimmune infections) and genomic instability.

Autophagy pathway

The basic pathway that autophagy follows begins with an isolated membrane called the phagophore . The phagophore expands and surrounds the targets or “cellular cargo” and sequesters them in its double membrane. The phagophore then fuses with a lysosome (in mammals, vacuoles in plants) which promotes degradation of the internal components by lysosomal proteases. The amino acids and other by-products of this step go to the cytoplasm where they can help build new molecules later on.

In technical terms, there are five stages that go into the orchestration of autophagy.

• Forms of phagophore
• Atg5-Atg12 proteins conjugate and interact with Atg16L within the phagophore.
• The LC3 protein is modified and inserted into its membrane.
• Targets are selected and degraded (but random things can also be taken).
• The autophagosome fuses with the lysosome and the engulfed molecules are broken down.

Phagophore formation begins with the fabrication of an isolated membrane, a key step since the function of the vesicle depends on its ability to absorb the contents. This process is organised around a structure called PAS (a pre-autophagic structure). In mammalian macroautophagy, the pathway taken by autophagy begins with an “initiation” step with PAS. The phagophore then begins “nucleation”, which is basically the circling of proteins and cytosolic organelles. Next, the phagophore matures into an autophagosome with the addition of LC3 to the membrane and “expansion” begins. The next step involves the fusion of a lysosome containing hydrolases. As a result, the contents inside are broken down into parts that can be recycled, a process called ‘nutrient recycling’.

Another remarkable fact about autophagy is that it was previously thought to be only a pro-death mechanism. This misconception arose from evidence showing its involvement in non-apoptotic death. But recent research suggests that it promotes life and survival rather than cell death. Autophagy occurs in all cells to maintain basal homeostatic conditions. Specifically, cells perform it to promote organelle turnover, especially when cells are starving and in need of nutrients. Factors that influence the control of autophagy are nutrition and hormones. oxygen and temperature. For example, autophagy was once thought exclusively to contribute to neurodegeneration, but recent research suggests that it may be a protective way of degrading toxic or malfunctioning proteins in neural cells.

Autophagy fasting

Autophagy has gained ground because of its relationship with exercise, diet and fasting. All of these elements put pressure on our bodies, which stimulates self-cleaning at the cellular level. With exercise, exercise creates tiny tears in our muscles which the body tends to do immediately with autophagy and cell renewal and recycling. This strengthens the affected muscles and makes them more resistant to future stressors. A study in mice showed that autophagosomes become increasingly numerous with thirty minutes of treadmill exercise (and even more so with eighty minutes).

In humans, this relationship is still being determined, but it certainly sets a precedent. Intermittent fasting has similar benefits. Insulin levels rise after a meal in most model organisms and there appear to be low rates of autophagy associated with high insulin levels. However, when insulin levels fall during fasting, autophagy rates increase in many folds in mice (and theoretically also in humans).

Young organisms have high autophagy rates, but with ageing, autophagy rates slow down and this allows cell damage and toxicity for kneading. Neuronal cells were also studied in fasted mice to test the effect of short-term fasting on neurodegeneration. Fasting saw an increase in the autophagosome count (via electron microscopy) and also reduced the ribosome phosphorylated Purkinje ribosome. All this attests to the homeostatic role of autophagy against degenerative pathways, which seems to be actively restored in times of fasting.