PINK1- and Parkin-mediated mitophagy at a glance

Topic: Disease mechanisms in lab and animal studies

Recently, work in cultured cells has shown that Parkin can mediate autophagy of damaged mitochondria (termed mitophagy) (Narendra et al., 2008) downstream of PINK1 (Geisler et al., 2010a; Matsuda et al., 2010; Narendra et al., 2010b; Vives-Bauza et al., 2010). These reports suggest that a quality control pathway maintains the mitochondrial homeostasis in many cell types, including in dopaminergic neurons, whose malfunction causes the motor deficits in PD. It was initially found that mitochondria are selectively engulfed by autophagosomes following a loss in membrane potential (Lemasters et al., 1998), suggesting that mitophagy mediates selective removal of damaged mitochondria. This idea has been supported by recent knockout mouse models, where loss-of-function of ATG7, which functions in the autophagy pathway, results in an accumulation of defective mitochondria in certain tissues (Komatsu et al., 2005; Wu et al., 2009). As Parkin has also been found to selectively bind only to damaged mitochondria it has been suggested that Parkin might mediate a quality control pathway of mitophagy.Parkin was initially identified as a cytosolic E3 ubiquitin ligase that is mutated in familial forms of PD (Kitada et al., 1998), and mutations in this protein are now known to be the most prevalent cause of autosomal recessive monogenic PD. Previously, it has been shown that inhibiting the fusion–fission cycle, by disrupting mitochondrial fission using a dominant-negative dynamin-related protein 1 (DRP1), prevents mitophagy, indicating the importance of fission in mitophagy (Twig et al., 2008). Alternatively, or additionally, the smaller size of mitochondria that results from inhibition of fusion might facilitate their encapsulation by autophagosomes. However, the in vivo relevance of the degradation of these additional OMM proteins remains unclear.It has been shown that Parkin-mediated mitophagy is reduced when the proteasome is inhibited by epoxomicin or MG132 (Chan et al., 2011; Tanaka et al., 2010). It has been shown that the levels of the 52-kDa processed form of PINK1 increase upon inhibition of the proteasome (Muqit et al., 2006), whereas that the levels of the 64-kDa full-length form of PINK1 increase upon treatment with the mitochondrial depolarizing agent valinomycin (Lin and Kang, 2008). Full-length 64-kDa PINK1 is imported to the IMM, and this step is associated with cleavage of the MTS sequence, to give a ~60-kDa form, by the mitochondrial processing peptidase (

@article{jin2012-22448035,
  author  = {Jin, Seok Min and Youle, Richard J.},
  title   = {{PINK1- and Parkin-mediated mitophagy at a glance}},
  journal = {Journal of Cell Science},
  year    = {2012},
  doi     = {10.1242/jcs.093849},
  pmid    = {22448035},
  url     = {https://doi.org/10.1242/jcs.093849}
}

Key findings

• Recently, work in cultured cells has shown that Parkin can mediate autophagy of damaged mitochondria (termed mitophagy) (Narendra et al., 2008) downstream of PINK1 (Geisler et al., 2010a; Matsuda et al., 2010; Narendra et al., 2010b; Vives-Bauza et al., 2010).
• These reports suggest that a quality control pathway maintains the mitochondrial homeostasis in many cell types, including in dopaminergic neurons, whose malfunction causes the motor deficits in PD.
• It was initially found that mitochondria are selectively engulfed by autophagosomes following a loss in membrane potential (Lemasters et al., 1998), suggesting that mitophagy mediates selective removal of damaged mitochondria.
• This idea has been supported by recent knockout mouse models, where loss-of-function of ATG7, which functions in the autophagy pathway, results in an accumulation of defective mitochondria in certain tissues (Komatsu et al., 2005; Wu et al., 2009).
• As Parkin has also been found to selectively bind only to damaged mitochondria it has been suggested that Parkin might mediate a quality control pathway of mitophagy.Parkin was initially identified as a cytosolic E3 ubiquitin ligase that is mutated in familial forms of PD (Kitada et al., 1998), and mutations in this protein are now known to be the most prevalent cause of autosomal recessive monogenic PD.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1242/jcs.093849
• PubMed: 22448035
• Original source →

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