Autophagy, which means "self-eating," is an intracellular degradation system that digests undesired cargo such as old or damaged organelles, unnecessary proteins, and pathogenic agents before releasing the macromolecular contents back into the cytosol. Autophagy is the process of sequestering cell organelles and cytoplasmic material into double-membrane vesicles called autophagosomes and delivering them to lysosomes for breakdown by lysosomal hydrolases. It was first described in 1963 by Christian de Duve.
Autophagy's Mechanism
In eukaryotes, autophagy is divided into three pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy. Although all three mechanistically distinct processes lead to lysosomal breakdown of cellular cargo, macroautophagy has received the greatest attention and is reviewed briefly here.
Macroautophagy is characterized by the encapsulation of cellular cargo into double-membrane vesicles called autophagosomes, which is conserved among eukaryotes. Autophagy-related (Atg) proteins that are recruited hierarchically to the phagophore assembly site or the preautophagosomal structure in yeast mediate the development of autophagosomes around the targeted cargo (PAS). Initiator protein complexes at the PAS aid in the de novo creation of a phagophore or isolation membrane, a double membrane structure with lipid components originating from the golgi-endosome system. Multiple cellular organelles, including the plasma membrane, are known to serve as origins for the formation of a phagophore in animals when a specific PAS-like structure has not been found. The separation membrane becomes a phagophore when more Atg proteins are recruited, and the phagophore finally fuses at its free ends to create an autophagosome, which now surrounds and sequesters the cargo. Autophagosomes go through a maturation phase as they go through the endocytic pathway before combining with lysosomes to generate autophagolysosomes. The autophagosome-delivered cellular cargo is then destroyed by lysosome hydrolytic enzymes, with the degradation products released back into the cytoplasm for cell usage.
The development of an autophagosome is not required for the other two autophagy mechanisms. The lysosome directly engulfs sections of the cytoplasm in microautophagy, whereas specialized chaperone proteins bind to the cargo and carry it across the lysosomal membrane for breakdown in chaperone-mediated autophagy.
Autophagy's Physiological Importance
Autophagy is a stress-management system as well as a means of homeostatic control in cells, hence it is regulated differently depending on the cell type. For example, in stress-free cells, a low level of autophagy ensures that old, damaged organelles and proteins are quickly digested and the digested contents are recycled back into the cytosol, ensuring that the availability of cellular components is regulated for diverse cellular functions. However, in response to various types of cellular stresses such as nutrient deprivation, oxidative stress, radiation, or anticancer therapy, the autophagic machinery is upregulated to quickly detoxify cells and increase cellular component recycling in order to keep up with increased cell function. Furthermore, autophagy is known to play a direct function in preventing apoptosis in both normal and pathological situations via regulating connections between the autophagy protein Beclin-1 and the apoptosis regulator Bcl-2. Excessive autophagy, on the other hand, can act as an alternative cell-death route in the absence of strict spatiotemporal regulation. As a result, autophagy dysregulation has been linked to the start and progression of diseases such as cancer, neurodegenerative and autoimmune disorders, and many others.
Autophagy and mechanical stress
Autophagy can be naturally regulated by mechanical stressors such as compression, stretching, or shear stress owing to fluid flow when it is working as a pro-survival process predominantly driven by stress. Several studies have demonstrated how cells adapt to mechanical stressors by controlling autophagy levels, and how this may have ramifications in both physiological and pathological circumstances. For example, when mechano-sensitive osteoblasts are stimulated by a mechanical stimulation such as exercise, their mineralization capacity is increased, resulting in improved bone production and remodeling. In this regard, new investigations on the UMR-106 rat osteoblast cell line have revealed an increase in autophagy during mineralization, implying a relationship between low bone density and a lack of the autophagy protein Atg5. These findings point to autophagy's role in controlling bone remodeling in response to mechanical stressors.
Another recent study found that cells respond to compressive forces by inducing autophagy. There was a transitory increase in the rate of autophagosome production after applying compressive pressures of up to 1kPa, which is within the range of normal physiological stresses experienced by cells. This temporary rise is thought to act as a cellular stress management strategy until the cell can adapt to physical changes in its surroundings. Excessive mechanical stressors, on the other hand, can have the opposite effect, suppressing autophagy. Human and mouse cartilage explants treated to high impact mechanical injuries underwent cell death, which was accompanied with a significant drop in expression of autophagy markers, according to a recent study by Carames et al. The use of rapamycin to pharmacologically stimulate autophagy prevented cell death, underscoring the importance of autophagy and mechanical stress in maintaining healthy cells.
