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 Singh"],"technology_type":["Data-dependent acquisition","Mass Spectrometry","Data-independent acquisition"],"software":[""],"submitter_keywords":["Mitochondria","Mitochondrial extracellular vesicles","Aortic valve calcification","Valvular interstitial cells","Lc-ms/ms"],"full_dataset_link":["https://www.ebi.ac.uk/pride/archive/projects/PXD072508"],"tissue":["Fibroblast","Aortic Valve"],"sample_protocol":["VICs incubated with CROT siRNA or scrambled siRNA were harvested from a single well of a 6-well plate, at 0, 1, 3, 7, 14 and 21 days after switching from NM to OM (or NM for controls). Cells were washed with PBS then scraped from wells using 100 µL RIPA buffer and sonicated on ice to lyse cells. Proteolysis was performed using the iST kit (PreOmics GmbH) with 20 µg protein input with subsequent steps following the manufacturer’s protocol. After evaporation, peptides were resuspended in 40 µL of LC-load buffer. Mouse aortic valves were isolated from the aortic root and all three leaflets from each aortic valve were collected into a single tube. RIPA lysis buffer with Halt™ Protease and Phosphatase Inhibitor Cocktail, EDTA-free (100X) (ThermoFisher, 78443) was added to each sample. Sample solution was ultra-sonicated by using the probe sonicator on ice. Aortic valve lysis solutions were incubated overnight at 37℃, 500 rpm. Using the sonicator bath, ultrasonicated tubes for 10 minutes in plastic rack. Proteolysis was performed using the iST kit (PreOmics GmbH) with subsequent steps following the manufacturer’s protocol (smaller volumes of LYSE and DIGEST). After evaporation, peptides were resuspended in 22 µL of LC load buffer."],"repository":["Pride"],"quantification_method":["Not available"],"modification":[""],"data_protocol":["Human VIC data – The spectral processing steps were analyzed using Proteome Discoverer (version 3.2, Thermo Fisher Scientific). The spectra were queried against the Uniprot human database (downloaded May 2025; 42,421 entries) using the SEQUEST-HT search algorithm. Trypsin (full) was set as the digestion enzyme, allowing up to 2 missed cleavages and a minimum peptide length of 6 amino acids. Oxidation (+15.995 Da) of methionine and acetylation (+42.011 Da) of the N-terminus were set as variable modifications. Carbamidomethylation (+57.021 Da) of cysteine was set as a static modification. Spectral search tolerances were 10 ppm for the precursor mass and 0.02 Da for HCD spectra. The peptide FDR was calculated using Percolator (target/decoy method, separate databases), and spectra were filtered based on a 1.0% FDR. Relative quantification was performed by the Feature Mapper and Precursor Ions Quantifier nodes. Chromatographic alignment was performed with a maximum retention time shift of 10 minutes, mass tolerance of 10 ppm and signal-to-noise minimum of 5. VIC samples were analyzed under 3 experimental conditions: normal medium with control siRNA (NM, siSCR), osteogenic medium with control siRNA (OM, siSCR), and osteogenic medium with CROT knockdown (OM, siCROT). For each condition, samples were collected at Day 0, 1, 3, 7, 14, and 21. Samples from all time points within the same condition were combined and treated as a single group for proteomic analysis to generate one consensus proteome per condition. This approach was employed to capture sustained, condition-dependent proteomic changes associated with osteogenic differentiation, while increasing proteome depth and robustness across biological replicates, rather than focusing on time point–specific dynamics. Each condition included 3 independent biological replicates (n = 3), corresponding to VICs isolated from 3 different donors.  Mouse valve data - The acquired peptide spectra were searched with Proteome Discoverer package (PD, Version 3.2) using the CHIMERYS node with the INFERYS 4.7.0 prediction model. The spectra were queried against the Uniprot mouse database (downloaded April, 2025; 63,095 entries). Trypsin/P was set as the digestion enzyme, allowing up to 2 missed cleavages and a peptide length of 7-30 amino acids (1-6 peptide charge). Oxidation (+15.995 Da) of methionine was set as a variable modification, and carbamidomethylation (+57.021 Da) of cysteine was set as a static modification. The fragment mass tolerance was 20ppm. The FDR for PSM confidence was 0.01 and 0.05, for strict and relaxed confidence, respectively. The quantification type was set to the default setting, MS2 Apex (Quan in all files). Quantification utilized unique peptides and razor peptides. Razor peptides were used to quantify only the protein with the most identified peptides and not for the other proteins they are contained in. Peptide abundance was normalized by total peptide amount, and each protein intensity was calculated using the sum of its peptide intensities. Only protein groups with high FDR confidence were used in analysis. Each protein group is represented by a single master protein (PD Grouping feature). A unique and razor peptides per protein for quantification was used. Mouse aortic valve proteomic analysis was performed in three groups: Crot⁺/⁺ Sham, Crot⁺/⁺ aortic valve wire injury (AVWI), and Crot⁻/⁻ AVWI. The number of biological replicates per group was n = 4 for Crot⁺/⁺ Sham, n = 7 for Crot⁺/⁺ AVWI, and n = 8 for Crot⁻/⁻ AVWI, where each biological replicate represents valves collected from an individual mouse. All samples were processed and analyzed individually, and protein quantification was performed at the protein group level. The differential proteomic analysis was done using the statistical software suite, Qlucore Omics Explorere (v10, Qlucore, Sweden)."],"omics_type":["Proteomics"],"labhead":["Elena Aikawa"],"instrument_platform":[""],"labhead_affiliation":["Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA, United States"],"submission_type":["COMPLETE"],"species":["Homo Sapiens (human)","Mus Musculus (mouse)"],"publication":["42093641 Itagawa R,Okui T,Tanaka T,Nakamura Y,Hosokawa D,Clift CL,Blaser MC,Kasai T,Weiss L,Turner ME,Billaud M,Aikawa M,Singh SA,Aikawa E Mitochondrial Extracellular Vesicles Enhance Aortic Valve Calcification Via Carnitine O-Octanoyltransferase. Arterioscler Thromb Vasc Biol. 2026 May 7 10.1161/ATVBAHA.126.324456"],"submitter_mail":["sasingh@bwh.harvard.edu"],"submitter_affiliation":["Brigham and Women's Hospital, Harvard Medical School"],"submitter_country":["United States"],"doi":["10.6019/PXD072508"],"pubmed_abstract":["<h4>Background</h4>Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator of mitochondrial dysfunction and vascular calcification; however, its role in calcific aortic valve disease is unknown. We investigated whether CROT promotes calcific aortic valve disease progression through the release of procalcific mitochondria-derived extracellular vesicles (mitoEVs).<h4>Methods</h4>Human valvular interstitial cells were isolated from aortic valves of patients with aortic stenosis (n=49; n=34 males, n=15 females). Calcification was induced with osteogenic medium and assessed by Alizarin red. Proteomics compared valvular interstitial cells cultured in normal medium or osteogenic medium following scramble or CROT siRNA to define CROT-dependent pathways. Mitochondrial function was evaluated by Seahorse XF analysis (oxygen consumption rate) and morphology by MitoTracker staining. Extracellular vesicles were isolated by ultracentrifugation and characterized using NanoSight Pro. In vivo, aortic stenosis was induced by aortic valve wire injury in <i>Ldlr</i><sup><i>-/-</i></sup><i>Crot</i><sup><i>+/+</i></sup> (Sham, n=12; aortic valve wire injury, n=19) and <i>Ldlr</i><sup><i>-</i></sup><sup><i>/-</i></sup><i>Crot</i><sup><i>-</i></sup><sup><i>/-</i></sup> (aortic valve wire injury, n=23) mice. Disease progression was monitored by echocardiography, and calcification was visualized using OsteoSense680EX imaging.<h4>Results</h4>CROT silencing significantly reduced osteogenic medium-induced calcification in valvular interstitial cells (<i>P</i><0.05). Proteomics revealed alterations in mitochondria-associated proteins following siCROT. Osteogenic medium-induced mitochondrial fragmentation and increased mitoEV release were attenuated by CROT silencing. Immunofluorescence revealed mitoEVs localized to calcified extracellular regions. In vivo, CROT deficiency reduced valvular calcification and attenuated aortic stenosis progression.<h4>Conclusions</h4>Osteogenic stress drives mitochondrial fragmentation and procalcific mitoEV release. CROT inhibition restores mitochondrial homeostasis, reduces mitoEV release and calcification, identifying CROT as a potential therapeutic strategy for calcific aortic valve disease."],"pubmed_title":["Mitochondrial Extracellular Vesicles Enhance Aortic Valve Calcification Via Carnitine O-Octanoyltransferase."],"pubmed_authors":["Itagawa Rei R, Okui Takehito T, Tanaka Takeshi T, Nakamura Yuto Y, Hosokawa Daiki D, Clift Cassandra L CL, Blaser Mark C MC, Kasai Taku T, Weiss Luisa L, Turner Mandy E ME, Billaud Marie M, Aikawa Masanori M, Singh Sasha A SA, Aikawa Elena E"],"additional_accession":[]},"is_claimable":false,"name":"Mitochondrial extracellular vesicles promote aortic valve calcification  via carnitine O-octanoyltransferase","description":"Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular morbidity and mortality with no effective medical therapy. We previously identified carnitine O-octanoyltransferase (CROT) as a mediator of mitochondrial dysfunction and vascular calcification. However, its role in CAVD remains unexplored. Here, we investigate whether CROT contributes to CAVD progression by promoting the release of pro-calcific mitochondria-derived extracellular vesicles (mitoEVs). Methods and Results: Human valvular interstitial cells (VICs) were isolated from aortic valves obtained from patients with aortic stenosis (AS; n=34 donors). VICs were cultured in osteogenic medium (OM) to induce calcification, which was evaluated by Alizarin Red staining. Proteomic analysis was performed to identify differentially abundant proteins between VICs cultured in normal medium (NM) and OM, with the goal of elucidating mechanisms linking CROT to VIC calcification. Mitochondrial function was assessed using the Seahorse XF Analyzer to measure oxygen consumption rate (OCR), and mitochondrial morphology was examined by MitoTracker staining. Extracellular vesicles (EVs) were isolated from VIC-conditioned media by ultracentrifugation and characterized for particle size and concentration using NanoSight Pro. In vivo, AS was induced in C57BL/6J, Ldlr⁻/⁻ Crot (Sham, n=12), Ldlr-/- Crot+/+ (Aortic valve wire injury; AVWI, n=19) and Ldlr-/- Crot-/- (AVWI, n=23). Disease progression was monitored by echocardiography, and aortic valve calcification was visualized using OsteoSense 680EX near-infrared fluorescence-based molecular imaging. OM–induced calcification in VICs was reduced by siRNA-mediated CROT silencing (siCROT; p<0.05). Proteomic analysis revealed that mitochondrial-associated proteins were markedly altered following siCROT silencing. Examination of mitochondrial morphology showed that OM culture induced marked mitochondrial fragmentation, which was restored by siCROT treatment. Western blotting and flow cytometry analyses indicated that OM-induced mitochondrial fragmentation promotes the release of mitoEVs from VICs, which in turn contributes to calcification. Immunofluorescence revealed mitoEVs within the extracellular space, colocalizing with calcification. In vivo, CROT deficiency attenuated the progression of AS in AVWI mouse model by reducing valvular calcification. Conclusion: Osteogenic stimulation disrupts mitochondrial dynamics in VICs, promoting the release of pro-calcific mitoEVs. This study identifies CROT as a key regulator of this process, where CROT inhibition restores mitochondrial homeostasis and suppresses VIC calcification. These findings highlight CROT as a promising therapeutic target for the treatment of CAVD.","dates":{"publication":"2026-05-13","submission":"2025-12-30"},"accession":"PXD072508","cross_references":{"TAXONOMY":["NEWT:330879","NEWT:377960","NEWT:1131","NEWT:35795","NEWT:2042546","NEWT:259447","NEWT:295546","NEWT:1334565","NEWT:625351","NEWT:258594","NCBITaxon:1280","NEWT:112503","NEWT:1129","NEWT:309807","NEWT:59753","NEWT:89184","NEWT:309800","NEWT:281395","NEWT:1211601","NEWT:876138","NEWT:44271","NEWT:193516","NEWT:2315688","NEWT:1073882","NEWT:6819","NEWT:475174","NEWT:428386","NEWT:1117","NEWT:498257","NEWT:10036","NEWT:32264","NEWT:1590","NEWT:10034","NEWT:33114","NEWT:1596","NEWT:661410","NEWT:638632","NEWT:224326","NEWT:376619","NCBITaxon:79857","NEWT:1096976","NEWT:3765","NEWT:3767","NEWT:1589","NEWT:135622","NEWT:4615","NEWT:672127","NEWT:35786","NEWT:1580","NEWT:399784","NEWT:96731","NEWT:656064","NEWT:1582","NEWT:1584","NEWT:36630","NEWT:1585","NEWT:383379","NEWT:418106","NCBITaxon:12721","NEWT:10029","NEWT:913645","NEWT:641809","NEWT:1392488","NEWT:38815","NEWT:317447","NEWT:4688","NEWT:7719","NEWT:5530","NEWT:868565","NEWT:135674","NEWT:79329","NEWT:30069","NEWT:12637","NEWT:59729","NEWT:2164133","NEWT:295105","NEWT:108061","NEWT:60711","NEWT:224308","NEWT:3347","NEWT:49928","NEWT:160621","NEWT:212790","NEWT:110368","NEWT:1310161","NEWT:77133","NEWT:145481","NEWT:1310165","NEWT:29058","NCBITaxon:79824","NEWT:410658","NEWT:5516","NEWT:44688","NEWT:44689","NEWT:498211","NEWT:347256","NEWT:5518","NEWT:398007","NEWT:1527468","NEWT:498217","NEWT:498216","NEWT:11320","NEWT:246196","NEWT:246197","NEWT:145458","NEWT:1310173","NEWT:44685","NEWT:161934","NEWT:1148","NEWT:5508","NEWT:3329","NEWT:419481","NEWT:5507","NEWT:410661","NEWT:1140","NCBITaxon:2157","NEWT:2066563","NEWT:1143","NEWT:1287689","NEWT:1094343","NEWT:1462472","NEWT:1336795","NEWT:644042","NEWT:150808","NEWT:1182590","NEWT:3712","NEWT:3711","NEWT:3714","NCBITaxon:37162","NEWT:2065263","NEWT:177437","NEWT:10891","NEWT:10418","NEWT:118698","NEWT:1616117","NEWT:118696","NEWT:34865","NEWT:52283","NEWT:28174","NEWT:284812","NEWT:8175","NEWT:43330","NEWT:1603293","NEWT:44664","NEWT:43346","NEWT:3702","NEWT:1245466","NEWT:3704","NEWT:244366","NEWT:1246791","NEWT:176597","NEWT:118694","NEWT:2850","NEWT:118691","NEWT:34871","NEWT:33548","NEWT:52299","NEWT:8165","NEWT:96794","NEWT:3708","NEWT:332648","NEWT:44670","NEWT:926571","NEWT:536231","NEWT:376219","NEWT:219813","NEWT:1510","NEWT:460519","NEWT:1515","NEWT:572307","NEWT:1432138","NEWT:1424507","NEWT:1194599","NEWT:272844","NEWT:1348799","NEWT:33995","NEWT:55784","NEWT:1303443","NEWT:9483","NEWT:485","NEWT:56636","NEWT:2499525","NEWT:2853422","NEWT:487","NEWT:1538553","NEWT:1679718","NEWT:480","NEWT:67767","NEWT:46835","NEWT:109757","NEWT:582580","NEWT:1185650","NEWT:216778","NEWT:1502","NEWT:128017","NEWT:376686","NEWT:237610","NEWT:95486","EFO:0001352","NEWT:119562","NEWT:1883446","NEWT:1233435","NEWT:118223","NEWT:11757","NEWT:987059","NEWT:109760","NEWT:29031","NEWT:317047","NEWT:1509","NEWT:491","NEWT:460523","NEWT:45954","NEWT:235443","NEWT:1579","NEWT:1757312","NEWT:85694","NEWT:109786","NEWT:108458","NEWT:5936","NEWT:320637","NEWT:1078283","NEWT:3750","NEWT:983964","NEWT:11706","NEWT:32644","NEWT:527796","NEWT:499175","NEWT:109779","NEWT:3745","NEWT:1715989","NCBITaxon:4751","NEWT:3747","NEWT:1116234","NEWT:1255228","NEWT:410289","NEWT:191701","NEWT:373153","NEWT:1640278","NEWT:472","NEWT:940825","NEWT:29459","NEWT:529507","NEWT:1071661","NEWT:28128","NEWT:470","NEWT:5911","NEWT:748693","NCBITaxon:50557","NEWT:39251","NEWT:29491","NEWT:101841","NEWT:446","NEWT:153481","NEWT:2014887","NEWT:33952","NEWT:11723","NEWT:445","NEWT:153009","NEWT:261756","NEWT:166313","NEWT:63366","NEWT:63367","NEWT:215402","NEWT:1547","NEWT:1290454","NEWT:906914","NEWT:28141","NEWT:9031","NEWT:27292","NEWT:1050722","NEWT:3728","NEWT:108931","NEWT:1293497","NEWT:1055524","NEWT:548","NEWT:150475","NEWT:267872","NEWT:381666","NEWT:172269","NEWT:9534","NEWT:2126348","NEWT:5180","NEWT:256737","NEWT:9541","NEWT:8694","NEWT:33936","NEWT:8692","NEWT:2903","NEWT:185579","NEWT:13076","NEWT:207340","NEWT:1006581","NEWT:8673","NEWT:33940","NEWT:550","NEWT:33941","NEWT:554","NEWT:451516","NEWT:552","NEWT:1325291","NEWT:42410","NEWT:36185","NEWT:1054211","NEWT:1225786","NEWT:771870","NEWT:51338","NEWT:9995","NEWT:575412","NEWT:28112","NEWT:49012","NEWT:6493","NEWT:10832","NEWT:6494","NEWT:6491","NEWT:507601","NEWT:520","NEWT:186441","NEWT:643680","NEWT:214092","NCBITaxon:6157","NEWT:13095","NEWT:162425","NEWT:104105","NEWT:216257","NEWT:9986","NEWT:8654","NEWT:8658","NEWT:1268063","NEWT:8657","NEWT:9983","NEWT:8655","NEWT:5147","NEWT:28108","NEWT:28104","NEWT:407821","NEWT:568703","NCBITaxon:2","NEWT:568708","NEWT:1613","NEWT:986","NEWT:52641","NEWT:28532","NEWT:353152","NEWT:298176","NEWT:353153","NEWT:227377","NEWT:1774284","NEWT:40674","NEWT:1194669","NEWT:74426","NEWT:443906","NEWT:13037","NEWT:519","NEWT:2510939","NEWT:7394","NEWT:6063","NEWT:1328388","NEWT:105487","NEWT:1548728","NEWT:667127","NEWT:9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