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

Colleen S Stein; Xiaoming Zhang; Nathan H Witmer; Edward Ross Pennington; Saame Raza Shaikh; Ryan L Boudreau

doi:10.1101/2024.05.31.596875

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

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

Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Saame Raza Shaikh and Ryan L Boudreau

bioRxiv : the preprint server for biology

Cold Spring Harbor laboratory

06/01/2024

DOI: 10.1101/2024.05.31.596875

PMCID: PMC11160723

PMID: 38853979

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https://doi.org/10.1101/2024.05.31.596875View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 Ca 2+ 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/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-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.

Details

Title: Subtitle: Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury
Creators: Colleen S Stein - University of Iowa
Xiaoming Zhang - University of Iowa
Nathan H Witmer - University of Iowa
Edward Ross Pennington - University of North Carolina at Chapel Hill
Saame Raza Shaikh - University of North Carolina at Chapel Hill
Ryan L Boudreau - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
Publisher: Cold Spring Harbor laboratory
DOI: 10.1101/2024.05.31.596875
PMID: 38853979
PMCID: PMC11160723
Language: English
Date posted: 06/01/2024
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Iowa Neuroscience Institute
Record Identifier: 9984642859002771

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