Mitophagy is a specific form of autophagy where mitochondria are specifically targeted for degradation by autophagolysosomes.. In mammals there are a number of known mechanisms of mitophagy. One insures maternal inheritance of mitochondrial DNA through the elimination of sperm derived mitochondria. A second is elimination of functional mitochondria during erythrocyte maturation and eye lens maturation. It is established that the outer mitochondrial membrane receptor Nix (or Bnip3l) and autophagosome associated protein LC3 are important for mitochondrial degradation in erythrocytes. A third mechanism is driven by the Pink1 and Parkin proteins. Parkin is recruited to the mitochondria when the mitochondrial membrane potential is reduced due to uncoupling, thereby initiating mitophagy.
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p62 links to the microtubule-associated protein Autophagy marker Light Chain 3 (LC3). This begins the recruitment of the autophagy machinery to the damaged mitochondria, targeting it for autophagic degradation.
Parkin promotes the ubiquitination of outer mitochondrial membrane emedded proteins including the mitofusin mitochondrial assembly regulatory factor (MARF), mitofusin 1, mitofusin 2 and voltage dependent anion selective channel protein 1 (vDAC1).
The mitochondria are engulfed after elongation of the isolation membrane. Once the autophagosome is formed, its outer membrane fuses with lysosomes to form the autolysosome. The lysosomal hydrolases (cathepsins and lipases) ultimately degrade the damaged mitochondria and its associated proteins.
On damaged mitochondria that have lost their membrane potential, however, PINK1 cleavage is inhibited, leading to high PINK1 protein accumulation on the inner leaf of the OMM of dysfunctional mitochondria. Full-length mitochondrial PINK1 is the active form in the PINK1/Parkin pathway.
Full-length PINK1 (63 kDa), which is in the inner mitochondrial space, is proteolytically cleaved into an 52-kDa cytosolic fragment (111 - 581) that is released back into the cytoplasm by an unknown mechanism and degraded by the proteasome. cleavage of PINK1 into an unstable cytosolic form maintains low levels of PINK1 on healthy mitochondria in order to suppress the PINK1/Parkin pathway in the absence of mitochondrial damage. At present, not all of the proteases mediating the cleavage of PINK1 in mammalian cells have been identified.
Parkin promotes the ubiquitination of the mitofusin mitochondrial assembly regulatory factor (MARF), mitofusin 1, mitofusin 2 and voltage-dependent anion-selective channel protein 1 (vDAC1), all of which are embedded in the OMM.
FUNDC1-mediated mitophagy is inhibited by its phosphorylation at the Serine 13 positions in the LIR motif by CK2kinase under normoxia conditions. These phosphorylation events insure that FUNDC1 cannot bind LC3.
ULK1 is critical for the induction of autophagy, translocating to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1.
Mitochondria are selectively removed by interactions between LC3 and the FUNDC1 mitophagy receptor which harbors an LC3-interacting region (LIR). When mitochondrial stresses are sensed mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia.
FUNDC1-mediated mitophagy is inhibited by its phosphorylation at the Tyr 18 position in the LIR motif by Src kinase under normoxia conditions. These phosphorylation events insure that FUNDC1 cannot bind LC3.
At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. FUNDC1 regulates ULK1 recruitment to damaged mitochondria; FUNDC1 phosphorylation by ULK1 is crucial for mitophagy.
The mitochondria are engulfed after elongation of the isolation membrane. Once the autophagosome is formed, its outer membrane fuses with lysosomes to form the autolysosome. The lysosomal hydrolases (cathepsins and lipases) ultimately degrade the damaged mitochondria and its associated proteins.
s17 Phosphorylated FUNDC1 links to the microtubule-associated protein Autophagy marker Light Chain 3 (LC3). This begins the recruitment of the autophagy machinery to the damaged mitochondria, targeting it for autophagic degradation.
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Mitophagy
Substrates:SQSTM1Annotated Interactions
Mitophagy
Substrates:SQSTM1Mitophagy
Substrates:SQSTM1