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Ubiquitin Project

The elucidation of molecular mechanisms underlying ubiquitin signaling and the related disorders Project

Project Leader Noriyuki Matsuda

Project Leader
Noriyuki Matsuda

Research Summary

Parkinson's disease (PD) is a common movement disorder characterized by loss of dopaminergic neurons. The majority of PD cases are sporadic, however, the discovery of genes linked to hereditary forms has provided important insights into molecular mechanisms associated with PD pathology. For example, functional analysis of recessive familial PD-related genes has identified a link between PD and mitochondrial quality control. However, the molecular mechanisms underlying this relationship have been obscure.

We focused on two genes associated with hereditary recessive PD, PINK1 and PARKIN. PINK1 encodes a Ser/Thr kinase and PARKIN encodes a RING-IBR protein. We found that when the mitochondrial membrane potential decreases, a sign of mitochondrial damage, PINK1 phosphorylates ubiquitin at Ser65. Phosphorylated ubiquitin activates the ubiquitin ligase (E3) function of Parkin (Koyano Nature 2014). Moreover, ubiquitin chains phosphorylated by PINK1 function as Parkin receptors and recruit Parkin to damaged mitochondria (Okatsu J.Cell.Biol. 2015). Consequently, the trio of PINK1, Parkin, and phospho-ubiquitin induced rapid ubiquitination of mitochondrial outer membrane proteins. Since a bewildering array of substrates are ubiquitinated by Parkin during this process, Parkin substrate specificity remained poorly understood. We found, using artificial mitochondria-targeted proteins, that substrate specificity of Parkin is not determined by specific amino acid sequences but instead by mitochondrial localization (Koyano J.Biol.Chem. 2019).

Ubiquitin is well-known for directing proteins for degradation. However, increasing evidence indicates that ubiquitination is also involved in quality control of larger structures including organelles, by tagging and directing damaged organelles for autophagic degradation. We found that ubiquitin chains on depolarized mitochondria are recognized by OPTN, an adaptor protein that recruits ATG9, a downstream autophagic protein, to damaged mitochondria (Yamano J.Cell.Biol. 2020). Impairment of this process prevents mitochondrial degradation and induces a predisposition to familial PD. Our work identifies a mechanism for PD pathology.

Schematic model for how PINK1, Parkin, and ubiquitin cooperate in the degradation of damaged mitochondria.

Schematic model for how PINK1, Parkin, and ubiquitin cooperate in the degradation of damaged mitochondria.

Selected Publications

  • Yamano K, et al.(2020) “Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy.” J. Cell Biology 219: e201912144.
  • Koyano F, et al.(2019) “Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL.” J Biol Chem 294: 10300-10314.
  • Koyano F, et al.(2019) “Parkin-mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes.” EMBO Rep. 20: e47728.
  • Yamano K, et al.(2018) “Endosomal Rab cycles regulate Parkin-mediated mitophagy.”eLif 7: e31326
  • Okatsu K, et al.(2015) “Phosphorylated ubiquitin chain is the genuine Parkin receptor.” J. Cell Biology 209: 111-128
  • Koyano F, et al.(2014) “Ubiquitin is phosphorylated by PINK1 to activate Parkin.” Nature 510: 162-166.