{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:47:56Z","timestamp":1782280076133,"version":"3.54.5"},"posted":{"date-parts":[[2024,5,23]]},"group-title":"Biophysics","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T00:00:00Z","timestamp":1716422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,5]]},"abstract":"<jats:p>Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we determined that CL molecules extensively engage with the paddle domain (PD) of mitochondrial fusion protein Optic Atrophy 1 (OPA1), which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between CL and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled CL probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of CL enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). This suggests that the partial replacement of CL by MLCL, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.<\/jats:p>","DOI":"10.1101\/2024.05.21.595226","type":"posted-content","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T10:50:25Z","timestamp":1716461425000},"source":"Crossref","is-referenced-by-count":6,"title":["Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1"],"prefix":"10.64898","author":[{"given":"Sirikrishna","family":"Thatavarthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Abriata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Meireles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly E.","family":"Zuccaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0483-7639","authenticated-orcid":false,"given":"Akhil Gargey","family":"Iragavarapu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela May","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Frank R.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Frost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-3975","authenticated-orcid":false,"given":"Matteo","family":"Dal Peraro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5409-3797","authenticated-orcid":false,"given":"Halil","family":"Aydin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024052623451174000_2024.05.21.595226v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.10.001"},{"key":"2024052623451174000_2024.05.21.595226v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0210-7"},{"key":"2024052623451174000_2024.05.21.595226v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2021.06.003"},{"key":"2024052623451174000_2024.05.21.595226v1.4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41580-018-0092-0","article-title":"Mitochondrial proteins: from biogenesis to functional networks","volume":"20","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2024052623451174000_2024.05.21.595226v1.5","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s42255-023-00783-1","article-title":"Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction","volume":"5","year":"2023","journal-title":"Nat Metab"},{"key":"2024052623451174000_2024.05.21.595226v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0133-0"},{"key":"2024052623451174000_2024.05.21.595226v1.7","doi-asserted-by":"crossref","unstructured":"A. Liu , F. Kage , A. F. Abdulkareem , M. P. Aguirre-Huamani , G. Sapp , H. Aydin , H. N. Higgs , Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51. Nat Cell Biol, 1\u201314 (2024).","DOI":"10.1038\/s41556-024-01400-3"},{"key":"2024052623451174000_2024.05.21.595226v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0211-2"},{"key":"2024052623451174000_2024.05.21.595226v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature21077"},{"key":"2024052623451174000_2024.05.21.595226v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06441-6"},{"key":"2024052623451174000_2024.05.21.595226v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06462-1"},{"key":"2024052623451174000_2024.05.21.595226v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1215233"},{"key":"2024052623451174000_2024.05.21.595226v1.13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0005-2736(76)90353-9","article-title":"Lipid composition and protein profiles of outer and inner membranes from pig heart mitochondria","volume":"419","year":"1976","journal-title":"Comparison with microsomes. Biochimica et Biophysica Acta (BBA) -Biomembranes"},{"key":"2024052623451174000_2024.05.21.595226v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2013.07.002"},{"key":"2024052623451174000_2024.05.21.595226v1.15","doi-asserted-by":"crossref","first-page":"8031","DOI":"10.3390\/ijms21218031","article-title":"Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer","volume":"21","year":"2020","journal-title":"IJMS"},{"key":"2024052623451174000_2024.05.21.595226v1.16","first-page":"582","article-title":"Cardiolipin remodeling and the function of tafazzin","volume":"1831","year":"2013","journal-title":"Biochimica et Biophysica Acta (BBA) -Molecular and Cell Biology of Lipids"},{"key":"2024052623451174000_2024.05.21.595226v1.17","first-page":"102","article-title":"Effects of lipids on mitochondrial functions","volume":"1862","year":"2017","journal-title":"Biochimica et Biophysica Acta (BBA) -Molecular and Cell Biology of Lipids"},{"key":"2024052623451174000_2024.05.21.595226v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/jb.173.6.2026-2034.1991"},{"key":"2024052623451174000_2024.05.21.595226v1.19","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-014-9748-x"},{"key":"2024052623451174000_2024.05.21.595226v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq088"},{"key":"2024052623451174000_2024.05.21.595226v1.21","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1016\/j.bbamem.2009.04.019","article-title":"The role of cardiolipin in the structural organization of mitochondrial membranes","volume":"1788","year":"2009","journal-title":"Biochimica et Biophysica Acta (BBA) -Biomembranes"},{"key":"2024052623451174000_2024.05.21.595226v1.22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102738"},{"key":"2024052623451174000_2024.05.21.595226v1.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608396113"},{"key":"2024052623451174000_2024.05.21.595226v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav1850"},{"key":"2024052623451174000_2024.05.21.595226v1.25","doi-asserted-by":"crossref","first-page":"e3001899","DOI":"10.1371\/journal.pbio.3001899","article-title":"The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding","volume":"20","year":"2022","journal-title":"PLoS Biol"},{"key":"2024052623451174000_2024.05.21.595226v1.26","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.1016\/j.molcel.2022.10.003","article-title":"Structure and functionality of a multimeric human COQ7:COQ9 complex","volume":"82","year":"2022","journal-title":"Mol Cell"},{"key":"2024052623451174000_2024.05.21.595226v1.27","first-page":"e008289","article-title":"Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy","volume":"14","year":"2021","journal-title":"Circ: Heart Failure"},{"key":"2024052623451174000_2024.05.21.595226v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-60457-w"},{"key":"2024052623451174000_2024.05.21.595226v1.29","first-page":"1375","article-title":"Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"43","year":"2015","journal-title":"J Alzheimers Dis"},{"key":"2024052623451174000_2024.05.21.595226v1.30","doi-asserted-by":"crossref","unstructured":"A. B. Chaves-Filho , I. F. D. Pinto , L. S. Dantas , A. M. Xavier , A. Inague , R. L. Faria , M. H. G. Medeiros , I. Glezer , M. Y. Yoshinaga , S. Miyamoto , Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis. Sci Rep 9, 11642 (2019).","DOI":"10.1038\/s41598-019-48059-7"},{"key":"2024052623451174000_2024.05.21.595226v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(83)90209-5"},{"key":"2024052623451174000_2024.05.21.595226v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320450309"},{"key":"2024052623451174000_2024.05.21.595226v1.33","doi-asserted-by":"publisher","DOI":"10.1007\/BF01799418"},{"key":"2024052623451174000_2024.05.21.595226v1.34","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.32.5.383"},{"key":"2024052623451174000_2024.05.21.595226v1.35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.718510"},{"key":"2024052623451174000_2024.05.21.595226v1.36","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s100380200030","article-title":"Novel missense mutation (R94S) in the TAZ (G4.5) gene in a Japanese patient with Barth syndrome","volume":"47","year":"2002","journal-title":"J Hum Genet"},{"key":"2024052623451174000_2024.05.21.595226v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200926"},{"key":"2024052623451174000_2024.05.21.595226v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10176"},{"key":"2024052623451174000_2024.05.21.595226v1.39","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200605043"},{"key":"2024052623451174000_2024.05.21.595226v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2017.03.013"},{"key":"2024052623451174000_2024.05.21.595226v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.08.011"},{"key":"2024052623451174000_2024.05.21.595226v1.42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200677200"},{"key":"2024052623451174000_2024.05.21.595226v1.43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400920200"},{"key":"2024052623451174000_2024.05.21.595226v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407043101"},{"key":"2024052623451174000_2024.05.21.595226v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.032"},{"key":"2024052623451174000_2024.05.21.595226v1.46","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s44318-024-00027-2","article-title":"In situ architecture of Opa1-dependent mitochondrial cristae remodeling","volume":"43","year":"2024","journal-title":"The EMBO Journal"},{"key":"2024052623451174000_2024.05.21.595226v1.47","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1016\/j.celrep.2017.05.073","article-title":"OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions","volume":"19","year":"2017","journal-title":"Cell Reports"},{"key":"2024052623451174000_2024.05.21.595226v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.03.011"},{"key":"2024052623451174000_2024.05.21.595226v1.49","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201308006"},{"key":"2024052623451174000_2024.05.21.595226v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3560"},{"key":"2024052623451174000_2024.05.21.595226v1.51","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50973"},{"key":"2024052623451174000_2024.05.21.595226v1.52","doi-asserted-by":"crossref","first-page":"e50294","DOI":"10.7554\/eLife.50294","article-title":"Cryo-EM structures of S-OPA1 reveal its interactions with membrane and changes upon nucleotide binding","volume":"9","year":"2020","journal-title":"eLife"},{"key":"2024052623451174000_2024.05.21.595226v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.11.003"},{"key":"2024052623451174000_2024.05.21.595226v1.54","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41594-022-00898-1","article-title":"Brominated lipid probes expose structural asymmetries in constricted membranes","volume":"30","year":"2023","journal-title":"Nat Struct Mol Biol"},{"key":"2024052623451174000_2024.05.21.595226v1.55","doi-asserted-by":"crossref","unstructured":"W. R. Arnold , A. Mancino , F. R. Moss , A. Frost , D. Julius , Y. Cheng , Structural basis of TRPV1 modulation by endogenous bioactive lipids. Nat Struct Mol Biol, 1\u20139 (2024).","DOI":"10.1038\/s41594-024-01299-2"},{"key":"2024052623451174000_2024.05.21.595226v1.56","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210708"},{"key":"2024052623451174000_2024.05.21.595226v1.57","doi-asserted-by":"publisher","DOI":"10.1021\/bi00260a035"},{"key":"2024052623451174000_2024.05.21.595226v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(98)77950-0"},{"key":"2024052623451174000_2024.05.21.595226v1.59","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.bbamem.2004.07.008","article-title":"Vesicle size-dependent translocation of penetratin analogs across lipid membranes","volume":"1665","year":"2004","journal-title":"Biochimica et Biophysica Acta (BBA) -Biomembranes"},{"key":"2024052623451174000_2024.05.21.595226v1.60","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1042\/BST20190932","article-title":"Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins","volume":"48","year":"2020","journal-title":"Biochemical Society Transactions"},{"key":"2024052623451174000_2024.05.21.595226v1.61","doi-asserted-by":"publisher","DOI":"10.1021\/bi00333a013"},{"key":"2024052623451174000_2024.05.21.595226v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.04.001"},{"key":"2024052623451174000_2024.05.21.595226v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)30583-5"},{"key":"2024052623451174000_2024.05.21.595226v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2024052623451174000_2024.05.21.595226v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2005.07.007"},{"key":"2024052623451174000_2024.05.21.595226v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2015.08.008"},{"key":"2024052623451174000_2024.05.21.595226v1.67","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"2024052623451174000_2024.05.21.595226v1.68","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nmeth.2727","article-title":"Quantifying the local resolution of cryo-EM density maps","volume":"11","year":"2014","journal-title":"Nat Methods"},{"key":"2024052623451174000_2024.05.21.595226v1.69","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01456"},{"key":"2024052623451174000_2024.05.21.595226v1.70","doi-asserted-by":"publisher","DOI":"10.1107\/s2059798319011471"},{"key":"2024052623451174000_2024.05.21.595226v1.71","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"2024052623451174000_2024.05.21.595226v1.72","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3330"},{"key":"2024052623451174000_2024.05.21.595226v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"2024052623451174000_2024.05.21.595226v1.74","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20945"},{"key":"2024052623451174000_2024.05.21.595226v1.75","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.6103568"},{"key":"2024052623451174000_2024.05.21.595226v1.76","doi-asserted-by":"publisher","DOI":"10.1021\/ct300646g"},{"key":"2024052623451174000_2024.05.21.595226v1.77","doi-asserted-by":"publisher","DOI":"10.1021\/ct9002114"},{"key":"2024052623451174000_2024.05.21.595226v1.78","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00513"},{"key":"2024052623451174000_2024.05.21.595226v1.79","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4067"},{"key":"2024052623451174000_2024.05.21.595226v1.80","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1021\/acs.jctc.1c00708","article-title":"PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations","volume":"18","year":"2022","journal-title":"J Chem Theory Comput"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.05.21.595226","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:56:30Z","timestamp":1782276990000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.05.21.595226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,23]]},"references-count":80,"URL":"https:\/\/doi.org\/10.1101\/2024.05.21.595226","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41467-025-63813-4","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,5,23]]},"subtype":"preprint"}}