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

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

doi:10.1093/cvr/cvag011

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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, Scott Hahn, Adam C Straub, Saame Raza Shaikh and Ryan L Boudreau

Cardiovascular research, PMID 77427

01/20/2026

DOI: 10.1093/cvr/cvag011

PMID: 41555203

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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/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.

cristae

Cyb5r3

permeability transition

docosahexaenoic acid

mitochondria

monolysocardiolipin

cardioprotection

ischemia-reperfusion

triglycerides

cardiolipin

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
Scott Hahn - University of Pittsburgh
Adam C Straub - University of Pittsburgh
Saame Raza Shaikh - University of North Carolina at Chapel Hill
Ryan L Boudreau - University of Iowa
Resource Type: Journal article
Publication Details: Cardiovascular research, PMID 77427
DOI: 10.1093/cvr/cvag011
PMID: 41555203
NLM abbreviation: Cardiovasc Res
ISSN: 0008-6363
eISSN: 1755-3245
Publisher: Oxford University Press
Grant note: American Heart Association: 23PRE1011277 University of Iowa Carver College of MedicineNIH NIDDK: P30DK056350 NIH NIGMS: T32GM067795 NIH NHLBI: R01HL144717, R01HL150557, R35HL177241, R35HL161177
This work was supported by the University of Iowa Carver College of Medicine (Distinguished Scholars Program to R.L.B.), NIH - National Heart, Lung, and Blood Institute (R01HL144717, R01HL150557, and R35HL177241 to R.L.B. and R35HL161177 to A.C.S.), NIH - National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056350 to S.R.S), NIH - National Institute of General Medical Sciences (predoctoral fellowship T32GM067795 to N.H.W), and the American Heart Association (23PRE1011277 to N.H.W.).
Language: English
Electronic publication date: 01/20/2026
Academic Unit: Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9985130061102771

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