Autophagy

The term autophagy goes back to the Belgian Nobel Prize winner Christian de Duve. In 2016, the Nobel Prize in Medicine was awarded to the Japanese researcher Yoshinori Ohsumi for his subtle research into the mechanisms of autophagy. Yoshinori Ohsumi received his PhD from the University of Tokyo in 1974, after which he spent three years at Rockefeller University in New York. He then returned to the University of Tokyo, where he established his own research group in 1988. In the early 1990s, he launched his pioneering studies on autophagy in yeast cells.

Autophagy (from Greek autóphagos =consuming itself) refers to a widespread and conserved intracellular lysosomal degradation process in eukaryotic cells that is upregulated in a starvation situation. In this process, cellular cytosolic material such as misfolded proteins or damaged cell organelles are degraded in a controlled manner (Saha S et al.2018). The nutrition-dependent regulation of mTOR (mammalian target of rapamycin) is an important determinant of autophagy.

The autophagy degradation pathway plays a fundamental role in cellular homeostasis and is mediated by evolutionarily conserved"autophagy-related (ATG) genes" (Levine B et al.2019). For example, a liver cell mitochondrion has a lifespan of 10 days before it is degraded by autophagocytosis(mitophagy). The regulated degradation of "cell detritus" prevents negative effects on cellular functions and ultimately restores molecules such as amino acids, fatty acids, or carbohydrates to the cell for anabolic processing. Overlap exists between autophagy, apoptosis, necrosis, and (D'Arcy MS 2019).

As a cell ages, autophagocytosis decreases, resulting in decreased formation of autophagic vacuoles and defective fusion of these vacuoles with lysosomes (Saha S et al.2018).

Basically, three different forms of autophagy are distinguished:

• Macroautophagy: Apparently, the first step in the formation of an autophagosome is the formation of a cup-shaped omegasome at the endoplasmic reticulum. This is the basis of the so-called phagophores, to which various ATG proteins (ATG= autophagy related) are attached step by step. The membrane structures formed in this way enclose cellular cargo that is to be disposed of. This tightly regulated assembly leads to the formation and eventual closure of the autophagosome.
• In a further step, the autophagosome fuses with a lysosome to form a so-called autophagolysosome. In the autophagolysosome, the enclosed particles are degraded by acid hydrolases. The fractionated basic building blocks can be made available for recycling. This mechanism helps to maintain cellular homeostasis.
• Microautophagy: smaller cytoplasmic components to be disposed of enter the interior of lysosomes by invagination of the membrane of lysosomes and subsequent strangulation, where they are degraded as in macroautophagy.
• Chaperone-mediated autophagy: This form of autophagy occurs with the aid of chaperones. Chaperones (or heat shock protein Hsc70) recognize cellular cargo to be disposed of and transfer it to a lysosome where it is degraded. Note: Altered chaperone-mediated autophagy is involved in the pathogenesis of PD (Kaushik S et al. 2018).

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Thus, the different forms of autophagy differ in the manner of cytosolic cargo delivery to the lysosome. Here, macroautophagy is the major catabolic mechanism used by eukaryotic cells to maintain nutrient homeostasis and organellar quality control. It is mediated by a set of evolutionarily conserved genes, the autophagy-related (ATG) genes (about 20 ATG genes have been reported to date) (Klionsky et al. 2003). With few exceptions, all ATG genes are required for the structural assembly of membrane-enveloped autophagosomes (Levine B et al. 2019).

Autophagy plays a role in a number of biological and pathological processes (Glick D et al. 2010):

Inflammatory bowel disease: Several autophagy genes, have been identified in inflammatory bowel disease, particularly Crohn's disease. Apparently, autophagy is critical for the maintenance of intestinal homeostasis, regulation of intestinal ecology, appropriate intestinal immune responses and antimicrobial protection. Dysfunctional autophagy leads to impaired intestinal epithelial function, intestinal dysbiosis with disturbances in antimicrobial peptide secretion by Paneth cells, and aberrant immune responses to pathogenic bacteria.

Dementia: accumulation of neurodegenerative plaques in dementia - impaired intracellular protein degradation.

Parkinson's disease: Mutations in the PARK2/Parkin and PARK6/PINK1 genes to the autosomal recessive and sporadic juvenile forms of the disease, respectively. The proteins resulting from these mutations label damaged mitochondria by marking a channel located on the surface of the mitochondria with the small protein ubiquitin. This marking serves as a signal for the cell to degrade the damaged organelles. If the PINK1 or Parkin proteins are missing due to a mutation, this disposal mechanism is impaired.

Muscle diseases: neuromuscular syndromes, myopathies

Innate and adaptive immune defenses: Autophagy is considered an important component of both innate and adaptive immune defenses. Xenoautophagy, a subtype of autophagy, is a very efficient defense mechanism against pathogenic germs, ideally destroying these germs. However, many pathogens bypass this defense mechanism. Others even use it to create a safe environment inside the cell in the vesicle that is strangulated by a membrane, where they can multiply undisturbed.

Autophagyand carcinogenesis: In the context of carcinogenesis, autophagy has been shown to play a still enigmatic role by serving as a tumor suppressor in the early stages, but later protecting tumor cells from immune system defense mechanisms (Saha S et al.2018). Thus, autophagy is considered one of the most important mechanisms that often allow few tumor cells to recover after prolonged chemotherapy or radiation. These form a reservoir for relapse. It is likely that autophagocytotic processes play a role in the resistance of leukemia cells (CML) to imatinib mesylate. Similarly, the resistance of HER2 positive breast carcinoma cells to trastuzumab and that of ovarian carcinoma to cisplatin appear to be due in part to autophagocytosis.

The potential of autophagy inhibition is currently being tested in numerous clinical therapeutic trials in solid tumors (Pasquier B (2016). In vitro studies showed that a hydroxychloroquine/ temsirolimus combination suppresses melanoma cells more than monotherapy.

Autophagy inhibitors: Among the best known autophagy inhibitors is hydroxychloroquine, which blocks the fusion of the autophagosome with the lysosome. Autophagy inhibitors include chloroquine, the tricyclic antidepressant clomipramine, and verteporfin. Sorafenib and the naturally occurring spermidine lead to increased autophagy.

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