positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of autophagy of the mitochondrion in response to mitochondrial depolarization. [GO_REF:0000058, GOC:pad, GOC:PARL, GOC:TermGenie, PMID:22020285]

Mitochondrial depolarization, a loss of the electrochemical gradient across the mitochondrial membrane, triggers a complex cellular response aimed at restoring homeostasis and preventing cell death. This response often involves the activation of autophagy, a process that degrades and recycles cellular components, including damaged mitochondria. This specific type of autophagy, targeting mitochondria, is known as mitophagy.

Here's a detailed breakdown of the biological process of positive regulation of autophagy of mitochondria in response to mitochondrial depolarization:

1. **Sensing Mitochondrial Depolarization:** The cell employs various mechanisms to detect the loss of membrane potential in mitochondria. Key sensors include:
* **PTEN-induced putative kinase 1 (PINK1):** In healthy mitochondria, PINK1 is rapidly degraded. However, upon depolarization, PINK1 accumulates on the mitochondrial outer membrane.
* **Parkin:** This E3 ubiquitin ligase is normally found in the cytosol. PINK1 recruits Parkin to the depolarized mitochondria, where it begins ubiquitinating mitochondrial proteins.
* **Other Sensors:** Additionally, the cell may utilize other sensors like reactive oxygen species (ROS) and Ca2+ levels to detect mitochondrial dysfunction.

2. **Ubiquitination Cascade:** Parkin, activated by PINK1, attaches ubiquitin chains to various proteins on the mitochondrial outer membrane. This ubiquitination signal serves as a "flag" marking the damaged mitochondria for destruction.

3. **Recruitment of Autophagy Machinery:** The ubiquitinated mitochondria become targets for autophagy receptors, such as p62/SQSTM1 and NDP52. These receptors bind to both the ubiquitin chains on the mitochondria and to the autophagic machinery.

4. **Formation of Autophagosomes:** The autophagy machinery, including LC3 and Atg proteins, assembles around the targeted mitochondria, engulfing them within a double-membrane vesicle known as an autophagosome.

5. **Fusion with Lysosomes:** The autophagosome then fuses with lysosomes, acidic organelles containing hydrolytic enzymes. These enzymes degrade the engulfed mitochondria, breaking them down into their constituent parts.

6. **Recycling and Homeostasis:** The breakdown products of the mitochondria are released into the cytosol, providing essential building blocks for the cell. This process helps restore cellular homeostasis and prevents the accumulation of damaged mitochondria.

7. **Regulation and Feedback Mechanisms:** The process of mitophagy is tightly regulated by a complex interplay of signaling pathways and feedback mechanisms. For example, mTOR signaling can inhibit autophagy, while AMPK activation can promote it.

This intricate process ensures that the cell can selectively remove damaged mitochondria, preventing their accumulation and the release of harmful substances, ultimately contributing to cell survival.
'"

Proteins (2)

Compounds (42)