Mitofusin-PD · Regulation of mitochondria-endoplasmic reticulum tethering by Parkin: implication for Parkinson’s disease

Parkin, an E3 ubiquitin ligase and a Parkinsons's disease related gene, translocates to impaired mitochondria upon mitochondria intoxication and drives their elimination via autophagy, a process known as mitophagy. Mitochondrial pro-fusion protein Mitofusin (Mfn) was found to be a target for Parkin mediated ubiquitination. In absence of Parkin, Mfn fails to be ubiquitinated, thus accumulates in the mitochondria, leading to increased mitochondria fusion. The host laboratory discovered that Mfn2 has an additional role in tethering mitochondria to endoplasmic reticulum (ER), a structural feature essential for Ca2+ transfer between the organelles and Ca2+ dependent cell death. This project hypothesizes that Parkin dependent ubiquitination of Mfn is crucial in regulating mitochondria-ER tethering and neuronal survival. We therefore aim to (i) address whether impairment of Parkin-dependent Mfn ubiquitination affects mitochondria-ER tethering and death by Ca2+-dependent stimuli; (ii) identify a potential Deubiquitinase (DUB) enzyme opposing Parkin activity in the regulation of Mfn ubiquitination; iii) identify novel interactors of the PINK1/Parkin pathway, regulating Parkin translocation to mitochondria and therefore Mfn steady-state levels. This project will therefore clarify if ER-mitochondria tethering participates in the neurodegenerative pathways controlled by Parkin