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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>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\u2013reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag011","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T12:53:19Z","timestamp":1768481599000},"page":"379-396","source":"Crossref","is-referenced-by-count":3,"title":["Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischaemia\u2013reperfusion injury"],"prefix":"10.1093","volume":"122","author":[{"given":"Colleen S","family":"Stein","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan H","family":"Witmer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Ross","family":"Pennington","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina , Chapel Hill, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C","family":"Straub","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1950-2521","authenticated-orcid":false,"given":"Saame Raza","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Gillings School of Global Public 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