# p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control

## TL;DR

This study shows how p62 protein helps cluster damaged mitochondria during cell cleanup, and how mutations in p62 may contribute to neurodegenerative diseases like ALS and FTD.

## Contribution

The study reveals that p62's phase separation drives mitochondrial clustering during mitophagy, acting as a brake to control mitochondrial turnover.

## Key findings

- p62 condensation forms grape-like clusters of damaged mitochondria during mitophagy.
- ALS/FTD-related mutations disrupt p62 condensation, impairing mitochondrial quality control.
- p62's role in clustering is distinct from other autophagy receptors like OPTN.

## Abstract

Mitochondrial quality control is tightly associated with aging‐related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD‐associated protein p62 drives “mitochondrial clustering” (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin‐mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form “grape‐like” clusters during PINK1/Parkin‐mediated mitophagy, which is tightly associated with aging‐related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a “brake” to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD‐related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the “brake” machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.

In normal PINK1/Parkin‐mediated mitophagy, unlike OPTN (the mitophagy receptor that mediates ATG8‐labeled autophagosome recruitment onto ubiquitinated mitochondria), p62 mediates the clustering of ubiquitinated mitochondria to form the “grape‐like” aggregates with ubiquitin. Under aging‐related neurodegenerative disease conditions, pathogenic mutants perturb p62 condensation, thereby destroying mitochondrial aggregation and impairing mitochondrial quality control.