# Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischaemia–reperfusion injury

## TL;DR

Mitoregulin, a small mitochondrial protein, helps maintain mitochondrial structure and protects the heart from injury during stress.

## Contribution

The study reveals Mitoregulin's role in stabilizing mitochondrial membranes and protecting against cardiac ischaemia–reperfusion injury.

## Key findings

- Mitochondria from Mtln-knockout mice are more vulnerable to membrane damage, which can be reversed by Mtln re-expression.
- Mtln stabilizes mitochondrial membranes by binding cardiolipin and influences lipid metabolism and cristae structure.
- Mtln-knockout mice show increased heart damage during ischaemia–reperfusion, suggesting a protective role in cardiac stress.

## Abstract

We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here, we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.

We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodelling. Finally, we demonstrate that Mtln-KO mice suffer worse myocardial ischaemia–reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.

Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.