Autophagy process in a fit guy for long lkife or longevity being depicted in a boy's shape

Autophagy Meaning and Definition

Autophagy (or autophagocytosis) is the natural, controlled process of the cells that removes unnecessary or dysfunctional parts. It enables cellular elements to be orderly degraded and recycled.

Three types of autophagy are frequently defined: Macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). In macroautophagy, expendable cytoplasmic components are focused and remoted from the rest of the cellular inside a double-membraned vesicle called an autophagosome. This, in time, fuses with an available lysosome, thereby bringing its forte technique of waste control and disposal. Subsequently the contents of the vesicle (now known as an autolysosome) are degraded and recycled.

Autophagy was seen in diseases as an adaptive response to stress, supporting the cell’s survival. In other instances, it appears to encourage cell death and morbidity. In the extreme case of hunger, the breakdown of cellular components encourages cellular survival by keeping cellular energy levels.

The name “autophagy” has existed and has been frequently used since the mid-19th century. In its current use, Belgian biochemist Christian de Duve invented the word autophagy in 1963 based on his discovery of lysosome activities. The identification of autophagy-related genes in yeast in the 1990s permitted scientists to deduce autophagy processes. This ultimately led to the award of the 2016 Nobel Prize in Physiology or Medicine to Japanese scientist Yoshinori Ohsumi.


  • History
  • Process and paths
  1.        Macroautophagy
  2.        Microautophagy
  3.        Autophagy mediated
  • Biology of molecule
  • Function
  •        Hunger for nutrient
  •        Xenophag
  •        Infection
  •        Repair mechanism
  •        Programmed cell death
  • Exercise
  • Osteoarthritis
  • Cancer
  •        Suppressor of tumor
  •        Survival of tumor cell
  •        Mechanism of cell death
  •        Therapeutic goal
  •        Negative autophagy regulator
  • Parkinson disease
  • Importance of autophagy as a drug target


History of Autophagy

Keith R. Porter and his student Thomas Ashford first observed autophagy at the Rockefeller Institute. They recorded an initial amount of lysosomes in rat liver cells after glucagon was added in January 1962. Also, they recorded that some displaced lysosomes to the center of the cell contained other cell organelles such as mitochondria. They called this autolysis after After Christian de Duve and Alex B. Novikoff. However, Porter and Ashford misinterpreted their information as lysosome formation ignoring the pre-existing organelles. Lysosomes could not be regarded cell organelles but the component of cytoplasm such as mitochondria and microbodies generated hydrolytic enzymes.

In 1963 Hruban, Spargo and collaborators released a comprehensive ultrastructural description of ‘focal cytoplasmic degradation’ referring to a 1955 German research of injury-induced sequestration. Spargo, Hruban and collaborators acknowledged three ongoing phases of lysosome maturation of the sequestered cytoplasm. Also, that the process was not restricted to injury states that worked under physiological circumstances for “cellular material reuse” and ‘organele disposal’ during differentiation. Inspired by this discovery, de Duve christened the “autophagy” phenomenon. Unlike Porter and Ashford, de Duve evolved the term as part of lysosomal function at the time of describing the role of glucagon as a significant inducer of liver cell degradation. He created with his student Russell Deter that lysosomes are accountable for glucagon-induced process. This was the first time that lysosomes were formed as the locations of intracellular autophagy.


Researchers on the process

Several groups of researchers separately found autophagy-related genes using the budding yeast in the 1990s. Notably, Yoshinori Ohsumi and Michael Thumm examined hunger-induced non-selective process. Meanwhile, Daniel J Klionsky found the cytoplasm-to-vacuole targeting (CVT) pathway, which is a type of selective auto-phagy. They quickly discovered that they were looking at fundamentally the same path, just from distinct perspectives. Initially, different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD) were given to the genes discovered by these and other yeast groups. In 2003, yeast scientists proposed a unified nomenclature to use ATG to indicate auto-phagy genes. Yoshinori Ohsumi was granted the 2016 Nobel Prize in Physiology or Medicine, although some have pointed out that the award might have been more inclusive.

With 21st century beginning, the field of autophagy studies experienced rapid development. Knowledge of ATG genes supplied researchers with more convenient instruments to dissect autophagy functions in human health and disease. In 1999, the group of Beth Levine released a landmark finding linking autophagy with cancer. To date, the connection between cancer and autophagy remains a major theme of auto-phagy studies. The roles of auto-phagy in neurodegeneration and immune defense have also gained significant attention. The first Gordon Research Conference on Autophagy was held in Waterville in 2003. In 2005 Daniel J Klionsky launched a scientific journal Autophagy. Monterey hosted the first Keystone Symposia Conference on Autophagy in 2007. Carol A Mercer produced a BHMT fusion protein (GST-BHMT) in 2008 that showed starvation-induced site-specific fragmentation in cell lines. The degradation of betaine homo-cysteine methyltransferase (BHMT), a metabolic enzyme, could be used to evaluate the flux of auto-phagy in mammalian cells.

The Brazilian author Leonid Bózio reflects auto-phagy as an existential issue in contemporary literature. Tempos Sombrios’ psychological drama describes characters consuming their own life in an inauthentic life.


Autophagy Process and paths

Three main types of autophagy:

  •        Macroautophagy
  •        Microautophagy
  •        Autophagy mediated

There are three primary kinds of autophagy, namely macroautophagy, microautophagy, and autophagy mediated by Chaperone. They are mediated by genes related to autophagy and their related enzymes. Macroautophagy is then split into selective and bulk autophagy. The auto-phagy of organellesis in specific autophagy; mitophagy, lipophagy, pexophagy, chlorophagy, ribophagy, and others.



It is the primary pathway used mainly to eradicate damaged cell organels or unused proteins. First, the phagophore engulfs the material that needs to be degraded around the organelle marked for destruction, which forms a double membrane known as an autophagosome. The autophagosome then moves to a lysosome through cytoplasm of the cell, and the two organelles fuse. Within the lysosome, autophagosome content is degraded via lysosomal acid hydrolase.



On the other side, microautophagy includes the immediate engulfment of cytoplasmic material into the lysosome. This happens through invagination, meaning the lysosomal membrane’s inward folding, or cellular protrusion.


Chaperone-mediated autophagy, or CMA

This is a very complicated and particular pathway that includes the hsc70-containing complex being recognized. It implies that a protein must contain the recognition site for this hsc70 complex that will allow it to attach to this chaperone, forming the CMA-substrate / chaperone complex. This complex then passes to the lysosomal membrane-bound protein that will recognize and bind with the CMA receptor, enabling it to enter the cell. Upon acceptance, the substratum protein is unfolded and translocated across the lysosomal membrane with the help of the lysosomal hsc70 chaperone. CMA is considerably distinct from other kinds of auto-phagy because it translocates protein material one by one. And also, it is highly selective about what content crosses the lysosomal barrier.



This is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. It is mediated in mammals by Atg32 (in yeast) and NIX and its regulator BNIP3. PINK1 and parkin proteins regulate mitophagy. The incidence of mitophagy is not restricted to the damaged mitochondria but also includes undamaged mitochondria.



This is the autophagy degradation of lipids, a function that has been shown to exist in both animal and fungal cells. However, the function of lipophagy in plant cells continues elusive. The target in lipophagy is lipid structures called lipid droplets (LDs), spheric “organelles” with a nucleus of primary triacylglycerols (TAGs) and a unilayer of phospholipids and membrane proteins. The primary lipophagic pathway in animal cells is through the phagophore, macroautophagy, engulfment of LDs. On the other side, microplipophagy represents the primary pathway in fungal cells and is particularly well researched in the budding yeast Saccharomyces cerevisiae. Lipophagy was first found in mice and released in 2009.


Biology of Molecules

Autophagy is performed by genes related to autophagy (Atg). Ten or more names were used before 2003, but fungal autophagy scientists after this stage developed a unified nomenclature. Atg or ATG is linked to autophagy. It doesn’t indicate a gene or protein.

Genetic tests performed in Saccharomyces cerevisiae recognized the first autophagy genes. These genes were functionally defined after their identification and their orthologs were recognized and studied in a multitude of distinct species.

Amino acid sensing and other signals such as growth factors and reactive oxygen species control the activity of protein kinases mTOR and AMPK in mammals. These two kinases control autophagy by inhibitory phosphorylation of the Unc-51-like kinases ULK1 and ULK2 (Atg1 mammalian homologues). Autophagy induction results in dephosphorylation and activation of ULK kinases. ULK is a component of a protein complex that contains Atg13, Atg101 and FIP200. ULK phosphorylates and activates Beclin-1 (Atg6 mammalian homologue), which is also component of a protein complex. The Beclin-1 autophagy-inducible complex includes the proteins p150, Atg14L and the phosphatidylinositol 3-phosphate kinase (PI(3)K) Vps34 class III. The active ULK and Beclin-1 complexes relocate to the site of autophagosome initiation, the phagophore, where they both add to the activation of downstream auto-phagy elements.


Further details

Once active, VPS34 phosphorylates the lipid phosphatidylinositol to generate 3-phosphate phosphatidylinositol (PtdIns(3)P on the phagophore surface. The produced PtdIns(3)P is used as a docking point for proteins with a PtdIns(3)P binding motif. WIPI2, a WIPI (WD-repeat protein interacting with phosphoinositides) protein family PtdIns(3)P binding protein, has lately been shown to bind Atg16L1 physically. Atg16L1 is a member of an E3-like protein complex that is engaged in one of two ubiquitin-like conjugation structures vital for autophagosome formation. Its WIPI2 binding recruits it to the phagophore and mediates its activity.

The first of the two ubiquitin-like conjugation processes engaged in autophagy covalently connects the ubiquitin-like Atg12 protein to Atg5. The resulting conjugate protein then binds Atg16L1 to create an E3-like complex that acts as part of the second ubiquitin-like conjugation mechanism. This complex connects and activates Atg3, which covalently attaches mammalian homologues of the ubiquitin-like yeast protein ATG8 (LC3A-C, GATE16, and GABARAPL1-3) to the lipid phosphatidylethanolamine (PE) on the surface of autophagosomes. Lipidated LC3 contributes to the closure of autophagosomes and allows the docking of particular cargo and adaptor proteins such as Sequestosome-1/p62. The finished autophagosome then fuses with a lysosome through various protein activities, including SNAREs and UVRAG.

Following the fusion, the LC3 is retained on the inner side of the vesicle and degraded along with the cargo, while the LC3 molecules attached to the outer side are cleaved off by Atg4 and recycled. The autolysosome contents are eventually degraded and their construction blocks are released from the vesicle through the action of permeases.



Hunger for nutrients

Autophagy has roles in different cellular functions. One specific instance is yeasts, where nutrient starvation induces an elevated amount of autophagy. This enables the degradation of unneeded proteins and the recycling of amino acids for the synthesis of proteins, crucial for survival. In greater eukaryotes, autophagy is caused in reaction to the nutrient depletion that happens in animals at birth after breaking off the trans-placental food supply, and also of nutrient-hungry cultured cells and tissues. Mutant yeast cells with decreased autophagic capacity quickly perish under circumstances that are deficient in nutrition. Studies on apg mutants indicate that autophagy via autophagic organs is indispensable for protein degradation in the vacuoles under starvation circumstances and that at least 15 APG genes are involved in yeast autophagy. A gene known as ATG7 has been involved in nutrient-mediated autophagy as mice trials have shown that hunger-induced autophagy has been impaired in atg7-deficient mice.



In microbiology, xenophagy is the autophagic degradation of dangerous debris. Cell autophagic machinery additionally plays an essential function in innate immunity. Intracellular pathogens, such as Mycobacterium tuberculosis (the bacterium that’s answerable for tuberculosis) are focused for degradation by means of the same cell equipment and regulatory mechanisms that concentrate on host mitochondria for degradation. By the way, this is similarly proof for the endosymbiotic hypothesis. This process generally leads to the destruction of the invasive microorganism, despite the fact that a few bacteria can block the maturation of phagosomes into degradative organelles known as phagolysosomes. Stimulation of auto-phagy in inflamed cells can assist triumph over this phenomenon, restoring pathogen degradation.



Vesicular stomatitis virus is thought to be taken from the cytosol by the autophagosome and translocated to the endosomes where a pattern recognition receptor called toll-like receptor 7 detects single-stranded RNA. Following activation of the toll-like receptor, intracellular signaling cascades are launched, resulting in induction of interferon and other antiviral cytokines. A subset of viruses and bacteria undermine the autophagic pathway to support their replication. Galectin-8 has lately been recognized as an intracellular “hazard receptor” capable of initiating autophagy against intracellular pathogens. When galectin-8 binds to a broken vacuole, it recruits an auto-phagy adapter which include NDP52 leading to autophagosome formation and bacterial degradation.


Repair Mechanism in Autophagy

Autophagy degrades damaged organelles, cell membranes and proteins, and electing against autophagy is believed to be one of the primary factors for the accumulation and aging of damaged cells. Autophagy and autophagy regulators are engaged in the reaction to lysosomal harm, often driven by galectins such as galectin-3 and galectin-8, which in turn recruit receptors such as TRIM16. And NDP52 plus directly affects mTOR and AMPK activity, although mTOR and AMPK prevent and activate autophagy, respectively.


Programmed cell death

One of the processes of programmed cell death (PCD) is connected with the appearance of autophagosomes and relies on proteins of autophagy. This type of cell death most probably corresponds to a process that was morphologically characterized as autophagic PCD. However, one issue that continually occurs is whether autophagic activity in dying cells is the cause of death or is an effort to avoid it. A causative connection between the autophagic mechanism and cell death has not been proven by morphological and histochemical research so far.

In reality, there have been powerful arguments lately that autophagic activity in dying cells may be a survival mechanism. Studies of insect metamorphosis have shown cells experiencing a type of PCD that appears distinct from other classes; these have been suggested as examples of autophagic cell death. Recent pharmacological and biochemical studies have suggested that longevity and deadly auto-phagy can be differentiated by the form and degree of regulatory signals during stress, especially after viral infection. Although promising, these results have not been studied in non-viral systems.


Exercise for Autophagy

Autophagy is crucial for basal homeostasi. It is also highly important to maintain muscle homeostasis during physical exercise. At the molecular level, autophagy is only partly understood. A mice research demonstrates that autophagy is essential for the ever-changing requirements of their dietary and power requirements, primarily through protein catabolism’s metabolic pathways. In a 2012 research performed by the University of Texas Southwestern Medical Center in Dallas, mutant mice (with a knock-in mutation of BCL2 phosphorylation locations to develop progeny showing ordinary levels of basal autophagy but lacking in stress-induced autophagy) were evaluated to challenge this hypothesis. Results revealed that these mice showed a reduction in endurance and modified glucose metabolism during acute practice compared to a control group.

Further research showed that skeletal muscle fibers of collagen VI knockout mice showed indications of degeneration owing to insufficient autophagy leading to accumulation of damaged mitochondria and excessive cell death. However, exercise-induced autophagy was ineffective. But when autophagy was caused artificially after exercise, accumulation of damaged organelles in collagen VI-deficient muscle fibers was avoided and cellular homeostasis was preserved. Both studies show that autophagy induction can contribute to the positive metabolic impacts of exercise and that it is vital to maintain muscle homeostasis during use, especially in collagen VI fibres.

Work at the Research center for Cell Biology, University of Bonn, has shown that a particular form of autophagy, i.e., chaperone-assisted selective autophagy (CASA), is caused in contracting muscles and is needed to maintain muscle sarcoma under mechanical stress. The CASA chaperone complex acknowledges mechanically damaged cytoskeleton elements and directs these parts to lysosomes for disposal through an ubiquitin-dependent autophagic sorting pathway. This is essential to maintain muscle activity.



Because autophagy reduces with age and age is a significant risk factor for osteoarthritis, it suggests the function of autophagy in the growth of this disease. Proteins engaged in autophagy are decreased in both human and mouse articular cartilage with age. In culture, mechanical injury to cartilage explants also decreased auto-phagy proteins.Autophagy is constantly triggered in ordinary cartilage, but it is affected by age and precedes cartilage cell death and structural harm. Thus, autophagy is engaged in a standard joint protective process (chondroprotection).



Cancer often happens when several distinct pathways that control cell differentiation are disrupted. Autophagy plays a significant role in cancer, both in defending against cancer and possibly contributing to cancer development. Autophagy can lead to cancer by encouraging the survival of tumor cells that have been starved or degrade apoptotic mediators through autophagy. Under such instances, the use of late-stage autophagy inhibitors (such as chloroquine) in cells that use autophagy to survive increases the amount of cancer cells killed by antineoplastic drugs.

Autophagy’s role in cancer has been extremely studied and evaluated. There is proof that emphasizes the function of auto-phagy as both a tumor suppressor and a factor in tumor cell survival. However, the latest study has shown that, according to several models, autophagy is more probable to be used as a tumor suppressor.


Suppressor of Tumors

Several studies were conducted with mice and variable Beclin1, a protein that controls autophagy. The mice were discovered to be susceptible to the tumor when the Beclin1 gene was modified to be heterozygous (Beclin 1+/-). But when Beclin1 was over expressed, tumor growth was inhibited. Anyhow, care should be taken when interpreting beclin mutant phenotypes and attributing the findings to a defect in auto-phagy. Beclin1 is usually needed for phosphatidylinositol 3- phosphate manufacturing and as such impacts various endosomal and lysosomal functions, including endocytic and endocytosis degradation of activated growth factor receptors.

In support of the possibility that Beclin1 influences cancer growth through an autophagy independent pathway is the fact that key auto-phagy factors that are not known to influence other cellular mechanisms. And are definitely also not known to influence cell proliferation and cell death, such as Atg7 or Atg5, show a very distinct phenotype when the corresponding gene is knocked out, which does not include tumor formation. Additionally, Beclin1’s complete knockout is embryonic deadly, whereas Atg7 or Atg5’s knockout is not.

Necrosis and chronic inflammation have also been shown to be restricted by autophagy, which helps safeguard against tumor cell formation.


Survival of tumor cells

Optionally, autophagy has also shown to play a significant role in tumor cell survival. Autophagy is usable in cancer cells as a manner to cope with cell stress. For instance, miRNA-4673 induction of autophagy is a pro-survival mechanism that increases the resistance of cancer cells to radiation. Once these genes linked to autophagy were inhibited, cell death was potentiated. Features of autophagy offset the rise in metabolic energy. These metabolic stresses include hypoxia, deprivation of nutrients, and increased proliferation. These stresses trigger autophagy to recycle ATP and retain the survival of cancer cells. This process has shown to allow ongoing development of tumor cells by keeping the output of cellular energy. By inhibiting auto-phagy genes in these tumor cells, tumor regression and prolonged survival of tumor-affected organs were discovered. In addition, autophagy inhibition has also shown to improve the efficacy of anticancer therapies.


Mechanism of cell death in autophagy

Cells that undergo severe stress experience cell death either through apoptosis or necrosis. Prolonged activation of autophagy leads to elevated protein and organele turnover. A high level above the survival limit can destroy cancer cells with an elevated apoptotic limit. This method can be used as a therapeutic therapy for cancer.


Therapeutic goal of autophagy

New advances in studies have discovered that targeted autophagy can be a feasible therapeutic option in the fight against cancer. As mentioned above, autophagy plays a role in both tumor suppression and tumor cell survival. The characteristics of autophagy can thus be used as a strategy for cancer prevention.

The first strategy is to cause this process and improve the characteristics of tumor suppression.

Second strategy is to inhibit this process and thereby cause apoptosis.


Strategies defined

This first strategy was evaluated by looking at dose-response anti-tumor impacts during autophagy-induced therapies. These therapies have shown that dose-dependent autophagy rises. It is also directly linked to the dose-dependent development of cancer cells. This information promotes the creation of therapies that will promote this process. Second, inhibiting the protein pathways directly known to cause auto-phagy may also serve as an anticancer treatment.

The second strategy is based on the concept that autophagy is a mechanism of protein degradation used to keep homeostasis and conclusions that autophagy inhibition often leads to apoptosis. Autophagy inhibition is riskier as it can lead to cell survival instead of the required cell death.


Negative autophagy regulators

Negative autophagy regulators such as mTOR, cFLIP, and EGFR are designed to operate in various phases of the autophagy cascade. Autophagic digestion end-products may also serve as a negative feedback regulatory mechanism to prevent extended exercise.


Parkinson Disease

Parkinson’s disease is a neurodegenerative disorder partly triggered by the brain and brain stem cells death in many nuclei, such as substantia nigra. This disease is described by the inclusion of a protein called alpha-synuclien or Lewy bodies in affected neurons that cells cannot break down. Auto-phagy is vital to neuronal survival. Without effective autophagy, the neurons collect and degrade ubiquitinated protein aggregates. These ubiquitinated proteins are proteins that have been labeled with ubiquitin to degrade. Synuclial allele mutations contribute to increased lysosome pH and inhibition of hydrolase.

As a consequence, the degrading ability of lysosomes is reduced. There are several genetic mutations involved in the disease, which include loss of function.

  •       PINK1
  •       Parkin

Loss of function in these genes can possibly lead to damaged mitochondrial accumulation and protein aggregates that can lead to cellular degeneration. Mitochondria are engaged in the disease of Parkinson. In idiopathic Parkinson’s disease, the disease is frequently triggered by cellular oxidative stress, dysfunctional mitochondria, autophagic changes and protein aggregation. These can further lead to swelling and depolarization of the mitochondria.


Importance of autophagy as a drug target

Since autophagy dysregulation involves in the pathogenesis of a wide spectrum of illnesses, excellent attempts are being made to recognize and characterize tiny synthetic or natural molecules that can control it.







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NB The write-up is based on the most prevalent media information and is not a medical advice. Consult your Authorized Cardiologist for any Medical Treatment.

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