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.

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.

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