positive regulation of autophagic cell death

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of autophagic cell death. [GO_REF:0000058, GOC:bhm, GOC:TermGenie, PMID:25736836]

Positive regulation of autophagic cell death is a complex biological process that involves a tightly regulated cascade of events leading to the programmed demise of a cell through the lysosomal degradation of its components. It plays a crucial role in maintaining cellular homeostasis and eliminating damaged or unwanted cells. Here's a detailed breakdown of the process:

1. **Initiation:** The process often starts with cellular stress signals, such as nutrient deprivation, hypoxia, oxidative stress, or pathogen invasion. These signals activate signaling pathways that converge on the formation of autophagosomes, double-membrane vesicles that engulf cellular components.

2. **Autophagosome Formation:** The formation of autophagosomes involves the coordinated action of several autophagy-related (ATG) proteins. Key players include:
- **ULK1 complex:** This complex is activated by upstream signaling pathways and initiates the formation of the phagophore, a precursor to the autophagosome.
- **PI3K complex:** This complex generates phosphatidylinositol-3-phosphate (PI3P), a lipid that serves as a docking site for other ATG proteins.
- **ATG9:** This protein acts as a carrier for membrane lipids needed for autophagosome expansion.
- **LC3:** This protein, also known as MAP1LC3, is conjugated to the autophagosome membrane and serves as a marker for autophagosome formation.

3. **Cargo Delivery:** Once formed, autophagosomes engulf cellular components, including damaged organelles, protein aggregates, and pathogens. The cargo selection process is selective and involves specific receptors that bind to targeted substrates.

4. **Fusion with Lysosomes:** The autophagosome then fuses with lysosomes, which are acidic organelles containing hydrolytic enzymes. This fusion event creates an autolysosome.

5. **Degradation and Recycling:** The hydrolytic enzymes within the autolysosome break down the autophagosome cargo into smaller molecules, such as amino acids and fatty acids. These molecules are then recycled back into the cell, providing building blocks for cellular metabolism or contributing to new autophagosome formation.

6. **Regulation:** The process of autophagic cell death is tightly regulated by various factors, including:
- **mTOR:** This protein kinase acts as a master regulator of autophagy, inhibiting its initiation under favorable conditions.
- **AMPK:** This kinase, activated by cellular stress, promotes autophagy by inhibiting mTOR and activating ULK1.
- **Beclin-1:** This protein is a critical component of the PI3K complex and plays a crucial role in autophagosome formation.
- **Bcl-2:** This protein family regulates both apoptosis and autophagy, with some members promoting autophagy while others inhibit it.

7. **Execution of Cell Death:** In certain situations, autophagic cell death can be the primary mode of programmed cell demise. This occurs when the cell encounters overwhelming stress that overwhelms its ability to repair and survive. The accumulation of autophagosomes and the degradation of essential cellular components eventually lead to cell death.

In summary, positive regulation of autophagic cell death is a highly regulated cellular process that involves the formation of autophagosomes, cargo delivery, lysosomal fusion, degradation, and recycling. This process is essential for maintaining cellular homeostasis and eliminating damaged or unwanted cells. Its dysregulation can contribute to various diseases, including cancer, neurodegenerative diseases, and infectious diseases. Understanding the molecular mechanisms of this process holds promise for developing novel therapeutic strategies targeting these diseases.'
"

Proteins (1)

Compounds (92)