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

Article: Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischaemia-reperfusion injury

Authors: Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau

Journal: Cardiovasc Res. 2026 Mar 26;122(3):379-396

Abstract:
Aims: 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.

Methods and results: 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.

Conclusion: 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.

Link to journal online: https://academic.oup.com/cardiovascres/article/122/3/379/8430285