Autophagy

Autophagy is a term of Greek origin meaning ‘eating yourself’, the highly conserved cellular mechanism in the recycling of long-lived proteins and damaged organelles. Autophagy is a degradation pathway that functions in all nucleated cells from yeast to humans and has critical importance in maintaining intracellular balance1. It was first discovered in rat liver epithelial cells by Christian de Duve in 1963. It has become a hot topic when the 2016 Nobel Prize in Medicine was awarded to Japanese scientist Yoshinori Ohsumi, who discovered and explained the mechanisms that regulate autophagy2.

 Autophagy is a catabolic process in which intracellular proteins and organelles are broken down in lysosomes. The autophagy pathway was first defined as the genetic struggle of yeasts to survive in the absence of nitrogen. It was later found that autophagy in new-born mice is a necessary mechanism for surviving food shortages. Thus, autophagy is an effective way to help the cell adapt to the stressful environment by recycling intracellular molecules in the absence of nutrients and maintaining cell balance3.

It requires more than 30 autophagy proteins to work in harmony to perform its cellular function1. The destruction of intracellular fat, sugar, long-lived proteins, and misfolded or precipitated proteins due to a disease-related mutation is dependent on autophagy. In addition, autophagy ensures the digestion and quality control of intracellular parasites and organelles such as mitochondria and the endoplasmic reticulum. This important intracellular destruction mechanism takes place in several steps: The nucleation of the autophagic vesicle (autophagosome), the elongation of the autophagic membranes and the surrounding of the targets to be destroyed by the membranes, the union of the autophagosomes with the lysosomes, and finally, the destruction that occur with the help of lysosomal enzymes1,2.

In conditions that may be harmful to the cell, such as starvation, inflammation, hypoxia, oxygen stress, and endoplasmic reticulum stress; It provides alternative building blocks and energy sources for cell metabolism by recycling nutrients. In this way, it plays a role in the survival of cells by adapting to difficult conditions4.

Because of all these functions, understanding how autophagy pathways work under basic and stress conditions is important for both cellular and organismal physiology and disease biology. The smallest abnormality in autophagy functions can affect the development and neurodegenerative diseases, metabolic diseases, infections, and many other diseases. Since mitochondria are of great importance for the health of cells, especially nerve cells, and the main destruction pathway of damaged mitochondria is mitochondrial autophagy, autophagy is an important factor in neurodegenerative diseases1,3.

It is thought that autophagy begins with a phagophore, derived from the lipid bilayer. This phagophore enlarges to immerse intracellular cargo such as protein deposits and damaged organelles, thereby immersing the cargo into a double-membrane autophagosome. The autophagosome, which has enclosed the cargo, fuses with the lysosome, causing the autophagosomal content to be destroyed by lysosomal acid proteases. Lysosomal permeases and transporters bring amino acids and other by-products to the cytoplasm. Thus, these amino acids and by-products can be reused for macromolecule formation and metabolism5.

Autophagy is divided into three categories according to the cargo (organelles, proteins) delivery route; macroautophagy, microautophagy, and chaperone-mediated autophagy.Macro-autophagy starts with the formation of structures called autophagic vesicles and these structures are added end to end to form autophagosomes. If there is a stress condition such as starvation, long-lived proteins or organelles       are surrounded by autophagic vesicles, and they form autophagosomes. After this stage, autophagosomes fuse with lysosomes, and their contents are degraded by lysosomal enzymes. In this way, subunits including amino    acids and fatty acids are created for re-use within the cell4

Figure: “Three types of autophagy (Macroautophagic, micro autophagy, and chaperon-mediated autophagy)”

Micro-autophagy is the autophagic process in the lysosomal membrane that invaginates randomly and differentiates as an autophagic tubule to surround the cytosolic fractions. Then this tubule merge with the lysosomal lumen and tubular cargo is degraded. Duve and Wattiaux had shown macro-autophagy and micro-autophagy in 1966 in rat livers however the difference between macro-autophagy and micro-autophagy appeared in 1983s4,2.

Chaperone-mediated autophagy is a catabolic process that cytosolic proteins having KFERQ-like (KFERQ: K, lysine; F, phenylalanine; E, glutamic acid; R, arginine; Q, glutamine) motifs are translocated to lysosome membrane and then into the lysosome by chaperone-dependent selection and degraded. In this process, unlike micro-autophagy and macro-autophagy, substrate protein can be taken into the lysosome and degraded without any vesicle formation.

The most important benefit of autophagy is working against the effects of aging at the cellular level. As stress increases in the cell, autophagy increases to protect the body. Thus, the toxic proteins produced in the cells are cleaned or, it extends the life span of the cells by regenerating a certain part of the cells. Since the autophagy process is also applied against viruses and bacteria, it also makes a significant contribution to the body’s immune system. In addition, autophagy has a very important place in the survival of nerve cells (neurons) that cannot divide. In this way, it is predicted that it can prevent the formation of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.

References:

  1. Kocatürk, Nur Mehpare, and Devrim Gözüaçık. “Otofaji ve nörodejeneratif hastalıklar (Autophagy and neurodegenerative diseases).” Türkiye Klinikleri Farmakoloji Özel Dergisi (Nörodejeneratif Hastalıklarda Yeni Yaklaşımlar Özel Sayısı) 5.1 (2017): 11-20.
  2.  KARTLAŞMIŞ, Kezban, Umut Kökbaş, and Levent KAYRIN. “Kanser Metabolizması ve Otofaji.” Arşiv Kaynak Tarama Dergisi 27.4 (2018): 388-396.
  3. Izmirli, Müzeyyen, Hasret Ecevit, and Bülent Göğebakan. “Yaşamak için Otofaji.” Arşiv Kaynak Tarama Dergisi 23.3: 411-419.
  4. Mizushima, Noboru. “Autophagy: process and function.” Genes & development 21.22 (2007): 2861-2873.
  5.  Ravanan, Palaniyandi, Ida Florance Srikumar, and Priti Talwar. “Autophagy: The spotlight for cellular stress responses.” Life sciences 188 (2017): 53-67.

Figure Reference: Kiriyama, Yoshimitsu, et al. “Induction of the expression of GABARAPL1 by hydrogen peroxide in C6 glioma cells.” stress 3 (2015): 5.

Inspector: Elif Böcü

Yorum bırakın

E-posta adresiniz yayınlanmayacak. Gerekli alanlar * ile işaretlenmişlerdir