# Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex

## TL;DR

This study shows how Parkin, a protein linked to Parkinson's disease, regulates calcium balance and communication between cell structures called ER and mitochondria.

## Contribution

The paper reveals a new role for Parkin in regulating ER-mitochondria contacts via the IP3R-Grp75-VDAC1 complex.

## Key findings

- Loss of Parkin increases ER-mitochondria associations and calcium flux, leading to mitochondrial dysfunction.
- Parkin interacts with the IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites.
- Parkin ubiquitinates IP3R to control calcium transfer and maintain MAM stability.

## Abstract

Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium homeostasis has been implicated in the pathogenesis of Parkinson's disease (PD). Parkin, a PD-associated E3 ubiquitin ligase, has been shown to regulate MAM integrity and calcium dynamics. However, the mechanisms of Parkin recruitment and its substrate specificity have not been well understood. This investigation has demonstrated that loss of Parkin enhances ER-mitochondria associations and leads to excessive calcium flux in MAM, resulting in abnormal mitochondrial permeability transition pore (mPTP) opening and decreased cell viability. Further, Parkin physically interacts with IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites, where it is recruited by IP3R-mediated calcium flux and mitophagy. More importantly, Parkin deficiency leads to the accumulation of IP3R levels, particularly in MAM region. In addition, Parkin fine-tunes the stability of the complex and ubiquitinates IP3R for degradation via the ubiquitin-proteasomal system, ensuring suitable calcium transfer. Taken together, our study reveals a novel role of Parkin in regulating ER-mitochondria contacts, providing insights into PD pathogenesis and potential therapeutic strategies targeting MAMs.