# The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk

## TL;DR

This paper reviews how the endoplasmic reticulum helps direct proteins to mitochondria in neurons, highlighting the role of organelle interactions in maintaining cellular function.

## Contribution

The paper provides a comprehensive review of the emerging role of ER-mitochondria contacts in mitochondrial protein targeting, particularly in neurons.

## Key findings

- ER-mitochondria contacts serve as platforms for mitochondrial precursor translation and transfer.
- Endolysosomes influence ER and mitochondrial proteostasis through organelle crosstalk.
- Disruption of ER-mediated protein targeting may contribute to neurodegeneration.

## Abstract

Neurons depend on tightly regulated spatial proteostasis to maintain function across their extended morphology. The endoplasmic reticulum (ER), traditionally known for its function in protein synthesis, folding, and trafficking, has long been recognized as a central platform for directing proteins to organelles of the secretory and endocytic pathways. In contrast, its involvement in the targeting of mitochondrial proteins, which are not directly connected to classical trafficking routes, remains less well understood and has only recently gained attention. Growing evidence implicates the ER in post‐translational delivery of mitochondrial precursors through mechanisms that integrate local translation, chaperone activity, and dynamic organelle contact sites. ER‐mitochondria contacts form dynamic platforms for precursor translation, stabilization and transfer, as exemplified by pathways such as ER‐SURF. Endolysosomes add an additional layer of regulation by influencing both ER function and mitochondrial proteostasis. However, how these processes are mechanistically coordinated, particularly in neurons with their complex architecture, remains incompletely understood. In this review, we synthesize the current understanding on ER‐mediated mitochondrial protein targeting, highlight the role of membrane contact sites between ER, mitochondria and endolysosomes, and discuss how chaperone networks and signaling pathways shape mitochondrial precursor handling. We further explore how disruption of these systems might contribute to neurodegeneration, positioning organelle crosstalk as a critical determinant of mitochondrial proteostasis and neuronal health.