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Signaling Pathways title  Autophagy pathway, a recycling system in cells

Autophagy pathway is an adaptive process in response to cellular stress as nutrient starvation, oxidative stress, hypoxia, protein aggregation... It prevents cell damage and promote cell survival. It is a crucial molecular pathway for the preservation of cellular and organismal homeostasis (1,2).

During this process, key autophagic factors (ATG) orchestrate the formation of a double-membrane vesicle, known as the autophagosome. This encapsulates cellular components and fuses with lysosomes, resulting in the degradation of its contents through the activities of lysosomal hydrolases. The control of these factors is very important to ensure cellular homeostasis (3).

In eukaryotes, there are two conserved autophagy pathways, macro-autophagy and micro-autophagy.
  • In macro-autophagy, a membrane structure resembling a cup, appears close to the endoplasmic reticulum (ER). It referred to as the phagophore or isolation membrane. It undergoes elongation, bending, and eventually closes through membrane fission.

    This leads to the formation of a double-membraned structure known as the autophagosome. This autophagosome encapsulates a portion of the cytoplasm. Subsequently, the autophagosome merges with lysosomes (or vacuoles in yeasts and plants), which break down the contents.

    The ULK complex is the central regulator in the beginning of macro-autophagy. It contains the scaffold protein FIP200 (also known as RB1CC1), ATG13, ATG101 and the serine/threonine kinases ULK1 or ULK2. Mainly, mechanistic target of rapamycin complex 1 (mTORC1) inhibits its activity.

  • In micro-autophagy, the endosomal or lysosomal membrane invaginates inward to directly capture part of the cytoplasm.

    Endosomal micro-autophagy, a form of micro-autophagy in mammalian cells, involves the formation of multivesicular bodies within endosomes.

    The endosomal micro-autophagy occurs naturally. It also triggers during early periods of amino acid starvation. This process helps break down certain proteins found in the cytoplasm. Specifically, adaptors involved in macro-autophagy, like SQSTM1, NDP52, NBR1, TAX1BP1, and NCOA4, which is responsible for ferritin (9).

Autophagy pathway mechanism

 
Overview of the autophagy process (4)
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Signaling Pathways title  Autophagy pathway dysfunction and diseases

The defect in the functions of autophagic processes marks many pathologies, including:
  • infectious diseases
  • cancer with pro- and anti-tumoral complex roles, notably in inflammation, cell migration...
  • neurodegenerative diseases like Alzheimer, Parkinson, Polyglutamine diseases, Neuropathies, Amyotrophic lateral sclerosis.
  • Heart diseases such as Cardiomyopathies, Ischemia‐reperfusion injury, Atherosclerosis...
  • Musculoskeletal disorders like Muscular diseases, Bone disorders, Pulmonary fibrosis, Cystic fibrosis
  • Pulmonary disorders, like Chronic obstructive pulmonary disease...
  • Kidney diseases, like Acute kidney injury, Diabetic kidney disease, Polycystic kidney disease, Kidney fibrosis...
  • Metabolic syndromes, like Obesity, Non‐alcoholic fatty liver disease, Type 2 diabetes... (4-6,8)

A recent study on replicative crisis suggests that autophagy is an integral component of the tumor suppressive crisis mechanism. The cancer onset requires a loss of autophagy function.

During the crisis, on the one hand, proteins linked to autophagy increases. This includes lysosomal-associated membrane protein 1 (LAMP1) and ATG5–ATG12 conjugate (for phagophore biogenesis). In addition to the lipidated form of microtubule-associated protein 1A/1B-light chain 3 (LC3), LC3-II (for phagophore expansion). On the other hand, the autophagy target polyubiquitin-binding protein P62 (also known as SQSTM1) decreases (7).
Autophagic_cell_death

 
Autophagic cell death restricts chromosomal instability during replicative crisis (7)
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Left: The 23 pairs of chromosomes of cells in which autophagy is functioning look normal and healthy with no structural or numerical aberrations (each color represents a unique chromosome pair).

Right: the chromosomes of cells in which autophagy is not functioning bypass crisis, showing both structural and numerical aberrations, with segments added to, deleted from, and/or swapped between chromosomes - a hallmark of cancer. [Salk Institute]
(1) Mizushima N. & Komatsu M. Autophagy: renovation of cells and tissues. Cell (2011) 147(4):728-741.
(2) Klionsky, D. Jet al. A comprehensive glossary of autophagy- related molecules and processes (2nd edition). Autophagy (2011) 7(11):1273-1294.
(3) Debnath J, et al. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. (2023);24(8):560-575.
(4) Dikic I. & Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. (2018) 19(6):349-364.
(5) Ma Y. et al. Autophagy and cellular immune responses. Immunity (2013) 39(2): 211-227.
(6) Kimmelman A. C. & White E. Autophagy and tumor metabolism. Cell Metab. (2017) 25(5): 1037-1043
(7) Nassour J & al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. (2019).
(8) Klionsky DJ, et al. Autophagy in major human diseases. EMBO J. (2021);40(19):e108863.
(9) Yamamoto H, et al. Autophagy genes in biology and disease. Nat Rev Genet. (2023);24(6):382-400.
 

  • Biomarker list

You can check the biomarker list included in this pathway, see below:

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