AUTOPHAGY PATHWAY, A CELLULAR RECYCLING SYSTEM

Autophagy pathway is an adaptive cellular process activatd in response to stressors like nutrient starvation, oxidative stress, hypoxia, protein aggregation... It plays a crucial role in preventing cell damage and promoting cell survival, making it essential for maintaining cellular and organismal homeostasis. This pathway helps cells adapt to changing environments by recycling damaged components and promoting longevity.

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Overview of the autophagy process.

MECHANISMS OF AUTOPHAGY PATHWAY: FORMATION OF THE AUTOPHAGOSOME

During autophagy, key autophagic proteins, known as ATG (autophagy-related genes), coordinate the formation of a double-membrane vesicle called the autophagosome. This vesicle encapsulates cellular components, which are later degraded when the autophagosome fuses with lysosomes. The degradation process is carried out by lysosomal hydrolases. Proper regulation of these factors is critical to ensure cellular homeostasis and to prevent damage to the cell.

TYPES OF AUTOPHAGY PATHWAY: MACROAUTOPHAGY VS MICROAUTOPHAGY

In eukaryotic cells, two primary forms of autophagy exist: macroautophagy and microautophagy. Each has distinct mechanisms and roles in maintaining cellular health.

Macro-Autophagy: The Formation of the Autophagosome.

In macro-autophagy, a membrane structure resembling a cup, known as the phagophore, forms near the endoplasmic reticulum (ER). This structure elongates and bends, eventually closing through membrane fission. The result is the formation of a double-membraned autophagosome that encapsulates cytoplasmic components. The autophagosome then fuses with lysosomes, where its contents are broken down and recycled.

Micro-Autophagy: Direct Cytoplasmic Capture by Endosomes

Micro-autophagy involves the direct capture of cytoplasmic material by the endosomal or lysosomal membranes. In mammalian cells, this form of autophagy can lead to the formation of multivesicular bodies within endosomes. Micro-autophagy is naturally triggered during periods of amino acid starvation and plays a role in the breakdown of certain proteins in the cytoplasm. Adaptors involved in macro-autophagy, such as SQSTM1, NDP52, NBR1, TAX1BP1, and NCOA4, are also involved in this process, particularly in the degradation of ferritin.

REGULATION OF MACROAUTOPHAGY: THE ROLE OF THE ULK COMPLEX

The ULK complex is crucial for initiating macro-autophagy and consists of the scaffold protein FIP200, ATG13, ATG101, and the kinases ULK1/ULK2. The activity of the ULK complex is tightly regulated by mTORC1, which inhibits its function under nutrient-rich conditions. When mTORC1 is active, it prevents ULK complex activation, halting autophagy. However, during nutrient starvation or stress, mTORC1 is inhibited, allowing the ULK complex to initiate autophagy. This ensures that macro-autophagy occurs only under appropriate conditions, maintaining cellular homeostasis. Additionally, AMPK can activate the ULK complex in response to low energy, further promoting autophagy when needed.

AUTOPHAGY DYSFUNCTION AND ITS ROLE IN DIESEASES

The dysfunction of autophagy, a vital cellular process, is associated with a wide range of diseases. The failure of autophagic processes can lead to or exacerbate conditions such as:

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...

Recent studies have highlighted the role of autophagy in the tumor suppressive crisis mechanism. During this crisis, autophagic proteins such as lysosomal-associated membrane protein 1 (LAMP1) and ATG5-ATG12 conjugates increase, contributing to the biogenesis and expansion of the phagophore. Meanwhile, the autophagy substrate P62 (SQSTM1), which is involved in polyubiquitin binding, decreases. The loss of autophagy function during this crisis can trigger the onset of cancer by failing to suppress tumor growth.

Autophagic cell death restricts chromosomal instability during replicative crisis.

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. J. et 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.

AUTOPHAGY SIGNALING PATHWAY BIOMARKER LIST

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at [email protected] to get started on your project.

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

Species : Homo sapiens (human)

Signaling Pathways	Product ref	Informations
Autophagy	AT1H1	List infos

Species : Mus musculus (mouse)

Signaling Pathways	Product ref	Informations
Autophagy	AT1M1	List infos

Species : Rattus norvegicus (rat)

Signaling Pathways	Product ref	Informations
Autophagy	*******	List In progress...

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
Autophagy	*******	List In progress...

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