Regulation of ER-mitochondria contacts by Parkin via Mfn2

Valentina Basso, Elena Marchesan, Caterina Peggion, Joy Chakraborty, Sophia von Stockum, Marta Giacomello, Denis Ottolini, Valentina Debattisti, Federico Caicci, Elisabetta Tasca, Valentina Pegoraro, Corrado Angelini, Angelo Antonini, Alessandro Bertoli, Marisa Brini, Elena Ziviani

Research output: Contribution to journalArticle

Abstract

Parkin, an E3 ubiquitin ligase and a Parkinson's disease (PD) related gene, translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy. Mitochondrial pro-fusion protein Mitofusins (Mfn1 and Mfn2) were found to be a target for Parkin mediated ubiquitination. Mfns are transmembrane GTPase embedded in the outer membrane of mitochondria, which are required on adjacent mitochondria to mediate fusion. In mammals, Mfn2 also forms complexes that are capable of tethering mitochondria to endoplasmic reticulum (ER), a structural feature essential for mitochondrial energy metabolism, calcium (Ca2+) transfer between the organelles and Ca2+ dependent cell death. Despite its fundamental physiological role, the molecular mechanisms that control ER-mitochondria cross talk are obscure. Ubiquitination has recently emerged as a powerful tool to modulate protein function, via regulation of protein subcellular localization and protein ability to interact with other proteins. Ubiquitination is also a reversible mechanism, which can be actively controlled by opposing ubiquitination-deubiquitination events. In this work we found that in Parkin deficient cells and parkin mutant human fibroblasts, the tether between ER and mitochondria is decreased. We identified the site of Parkin dependent ubiquitination and showed that the non-ubiquitinatable Mfn2 mutant fails to restore ER-mitochondria physical and functional interaction. Finally, we took advantage of an established in vivo model of PD to demonstrate that manipulation of ER-mitochondria tethering by expressing an ER-mitochondria synthetic linker is sufficient to rescue the locomotor deficit associated to an in vivo Drosophila model of PD.

Original languageEnglish
Pages (from-to)43-56
Number of pages14
JournalPharmacological Research
Volume138
DOIs
Publication statusPublished - Dec 1 2018

Keywords

  • Drosophila model of PD
  • ER-mitochondria synthetic tether
  • ER-mitochondria tethering
  • Mitochondria
  • Mitofusin
  • Parkin
  • Parkinson's disease
  • PINK1
  • Ubiquitination

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Basso, V., Marchesan, E., Peggion, C., Chakraborty, J., von Stockum, S., Giacomello, M., Ottolini, D., Debattisti, V., Caicci, F., Tasca, E., Pegoraro, V., Angelini, C., Antonini, A., Bertoli, A., Brini, M., & Ziviani, E. (2018). Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacological Research, 138, 43-56. https://doi.org/10.1016/j.phrs.2018.09.006