# In and out of the mitochondrial intermembrane space

## TL;DR

This review explains how proteins are sorted into the mitochondrial intermembrane space and its role in maintaining mitochondrial function.

## Contribution

The paper provides a comprehensive overview of protein sorting mechanisms and proteostasis in the mitochondrial intermembrane space.

## Key findings

- The intermembrane space is a hub for monitoring mitochondrial proteins and ensuring proper folding.
- Most mitochondrial proteins pass through the IMS, where misfolded proteins are retrotranslocated and degraded.
- IMS-resident proteins are crucial for cellular processes like redox regulation and apoptosis.

## Abstract

Mitochondria are essential organelles constituted by two membranes, the outer (OMM) and inner mitochondrial membrane (IMM), and two aqueous compartments, the intermembrane space (IMS) and the matrix. Although mitochondria contain their own genome, which encodes for 13 proteins in humans (8 in budding yeast), the vast majority (99%) of mitochondrial proteins are encoded by the nuclear DNA and imported into the organelle co‐ or post‐translationally. The IMS lies between the cytosol and the matrix, making it a strategic hub for monitoring the mitochondrial proteome. All IMS‐resident proteins are nuclear‐encoded and play critical roles in cellular pathways, such as redox regulation, calcium signaling, apoptosis, and hypoxia response. Furthermore, most mitochondrial proteins pass through the IMS en route to their final destination within the organelle. During this transit, their targeting and folding states are carefully monitored: properly folded proteins are retained, while misfolded or potentially toxic polypeptides are retrotranslocated and degraded. In this review, we highlight the mechanisms by which proteins are sorted into the IMS and discuss its central role in regulating mitochondrial proteostasis and maintaining mitochondrial function.