Homeostasis, i.e. the ability of a cell to maintain a constant internal environment, is essential for cell survival. It is based on achieving a balance between the processes of production and degradation of cell components. An important metabolic route is autophagy, an intracellular program for breaking down and recycling superfluous or dysfunctional cell components.

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Autophagy, (from ancient Greek Aatüfägähós Autophagos “self-eating”), also known as “self-consumption,” is a highly conserved adaptive response to stress. This ancient defense mechanism binds protein aggregates, pathogens, and damaged or inoperative organelles into bubble-like structures within the cell called autophagosomes, and then releases them for destruction to release macromolecules such as proteins, fats, carbohydrates, and nucleic acids for energy production and reuse. The main goal of autophagy is to enable the cell to adapt to changing conditions and external stressors.

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Autophagy is different from apoptosis, a type of cellular self-destruction mechanism that rids the body of damaged or aged cells. However, the two processes are controlled by common signals and have common regulatory components, blurring the lines between their activities. In a simple analogy, where autophagy is the first answer and apoptosis is the executor, autophagy attempts to mitigate cell damage, but when it is unsuccessful, apoptosis occurs to kill the cell.

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The process of autophagy is activated by cellular stressors, such as nutritional deficiencies, hypoxia, and the presence of toxins, and involves a wide variety of genes, proteins, receptors, and signal transduction pathways.

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Although autophagy takes place at the cellular level, activating it at the whole body level can improve metabolic fitness and extend life span. [1] [2]

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Categorization and types of autophagy

In general, autophagy is categorized as either non-selective or selective.

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Non-selective autophagy

Non-selective autophagy can occur as part of the cell's normal physiological function (known as basal autophagy) or as a response to nutritional deficiencies or other stressors as a means of maintaining homeostasis. In this way, non-selective autophagy performs a general household function and maintains cellular quality control.

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Selective autophagy

Selective autophagy, on the other hand, targets specific units in the cell to be destroyed and removed and helps improve general cell function. This differentiated form of autophagy is based on evidence from damaged organelles, pathogens, or protein aggregates, which delimit them for destruction. It serves as a targeted cleaning program that removes easily damaged or aging parts of the cell.

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Types of autophagy

Several types of autophagy have been identified, which differ in how and when they are triggered, which method of sequestration they use, and which target they destroy. Two selective forms of autophagy are of particular interest: mitophagy and xenophagy.

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Mitophagy

Mitophagy involves the selective breakdown of mitochondria. It helps the body's cells to have an efficient metabolism without producing excessive amounts of reactive oxygen species — a type of oxidative stress that occurs naturally during metabolism and whose effects are reinforced by damaged mitochondria. Mitophagy ultimately serves as a trigger for mitochondrial biogenesis, i.e. the process by which new mitochondria are produced. Mitophagy disorders are linked to several chronic diseases, including cardiovascular disease, kidney disease, and Alzheimer's disease. [3] [4] [5]

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Xenophagia

Xenophagia is a function of the innate immune system. It targets foreign pathogens (such as bacteria or viruses), regulates the activation of antigens, and induces innate immune memory — a vital process in which immune cells “remember” threats. Xenophagia may also play a role in regulating cellular levels of non-microbial substances, such as iron [6].

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Autophagy triggers

Autophagy is primarily triggered by three signals, all related to the recognition of nutrients. The decline in cellular acetyl-CoA levels, an end product of nutrient metabolism, is crucial for each of these pathways. Acetyl-CoA alters the acetylation status of key proteins involved in autophagy (e.g. mTOR and AMP kinase) and thus serves as a common regulator for the many pathways that lead to their induction or inhibition.

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Starvation

When food is abundant, nutrient recognition pathways signal the body to create new components and store excess nutrients. However, when there is a shortage of food and the associated reduction of acetyl-CoA, homeostatic mechanisms are activated - such as the mobilization of stored nutrients through autophagy. When mice or human subjects starve, autophagy can be observed at a full body level [7].

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Imitating calorie restriction or fasting-mimicking

Acetyl-CoA levels can also be modulated by nutrient deprivation or by imitating calorie restriction, i.e. by compounds that cause cells to activate autophagy even when there is sufficient supply of nutrients [8]. Examples of imitating calorie restriction include resveratrol, metformin, and rapamycin [9].

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Sporting activity

Exercise is generally known for its numerous health benefits, including extending life span and protecting against cardiovascular disease, diabetes, cancer, and neurodegenerative diseases. Movement induces autophagy in the brain and in several organs involved in metabolism. These include the liver, pancreas, adipose tissue, and muscles, which could explain how exercise affects the entire body. [10] In particular, endurance training induces autophagy in mice and mediates the damaging effects of diabetes and obesity. [11]

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Physiological tasks of autophagy

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Immune system monitoring

In addition to its role as quality control and homeostasis managers, autophagy serves as a trigger for immune surveillance, a process by which immune cells detect and identify foreign pathogens such as bacteria, viruses, and precancerous or cancerous cells in the body.

Immune monitoring is activated when autophagy facilitates the release of ATP from dying cells, which attracts myeloid cells' attention. This critical factor of the body's immune system is largely responsible for innate defense against a range of pathogens. The released ATP activates a special class of cellular proteins called purinergic receptors, which in turn activate various elements of the immune system, including the inflammasome, an important player in the body's inflammatory response. [12] Immune monitoring is crucial for suppressing tumour development and subsequent growth. Their activation is a predictor of the long-term success of chemotherapy treatments and could help explain the complex relationship between autophagy and cancer. [13]

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Delayed aging

There is growing evidence that autophagy can contribute to longevity and health. Calorie restriction, a powerful trigger of autophagy, extends the life span of many organisms but also lowers the risk of many age-related chronic diseases such as diabetes, cardiovascular disease, cancer, and brain atrophy, which is likely due to the positive effects of autophagy. [14] [15]

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Pathophysiological role of autophagy

Autophagy disorders are associated with the development of cancer, autoimmune diseases, infectious diseases, and neurodegenerative diseases. A common factor in all of these conditions is inflammation. The impaired autophagy promotes the production of inflammatory messenger substances, which can lead to an inappropriate activation of the immune system and subsequent diseases.

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Cancer

While autophagy promotes suppression during tumorigenesis, it provides decisive protection during tumour development. In early-stage cancer, the initial suppression of autophagy may help prevent the immune system from becoming overly aware of it, but it may also facilitate ongoing transformation. In later stages of cancer, autophagy can help cancer cells survive in the tumor's hostile microenvironment. Metabolic stress is relatively well tolerated by cancer cell lines as they are able to activate the autophagic response [13].

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Autoimmune disease

Although autophagy is generally considered a beneficial process, it can have harmful effects in autoimmune diseases. In rheumatoid arthritis, a pro-inflammatory cell signaling protein triggers autophagy and promotes the differentiation of osteoclasts, a type of bone cell that breaks down mineralized tissue in the joint and thus destroys joint architecture. [16] Similarly, dysregulation of autophagy signaling has been found in lupus and Crohn's disease. [17]

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Infectious diseases

Some pathogens have developed strategies to successfully evade autophagy. For example, M. tuberculosis, the bacterium responsible for tuberculosis, controls autophagy mechanisms by hiding in the autophagosome and thus interfering with the processes to break down the pathogen. [18] The bacterium can also interfere with one of the steps involved in xenophagy and thus ultimately impair the body's immune response. [19] Similarly, the human immunodeficiency virus (HIV) reduces cellular levels of Key proteins involved in the induction of xenophagy. [20]

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Neurodegenerative disease

Mitophagy disorders are strongly associated with Parkinson's disease, a neurodegenerative disorder characterized by mitochondrial dysfunction and energy deficiencies in dopaminergic neurons in the brain. More and more evidence suggests that mitophagy is impaired in Parkinson's disease and promotes the accumulation of dysfunctional mitochondria. Impaired mitophagy is likely to contribute to the accumulation of misfolded proteins, which in turn impairs mitochondrial homeostasis [21].

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Autophagy is a complex process that influences many aspects of health and illness. It plays a crucial role in maintaining cellular homeostasis by participating in cell metabolism, survival, and defense of the carrier. Autophagy disorders are associated with a wide range of chronic conditions, including cancer, autoimmune disorders, neurodegenerative diseases, and aging. Modulation of autophagy could be a promising therapeutic approach to extend the human life and health span.