@article{bdee0fe5fec8413f9f47facd5101df3c,
title = "Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation",
abstract = "Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signaling. The specific role of EL in cardiac atrial fibrillation (AF) is not well understood. We isolated atrial EL organelles from AF goat biopsies and conducted a comprehensive integrated omics analysis to study the EL-specific proteins and pathways. We also performed electron tomography, protein and enzyme assays on these biopsies. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates, including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophagic-vacuole formation, irregularly shaped mitochondria, and glycogen deposition. Our results provide molecular information suggesting EL play a role in AF disease process over extended time frames.",
keywords = "Cell biology, Molecular biology, Proteomics, Transcriptomics",
author = "Thamali Ayagama and Charles, {Philip D.} and Bose, {Samuel J.} and Barry Boland and Priestman, {David A.} and Daniel Aston and Georgina Berridge and Roman Fischer and Cribbs, {Adam P.} and Qianqian Song and Mirams, {Gary R.} and Kwabena Amponsah and Lisa Heather and Antony Galione and Neil Herring and Holger Kramer and Capel, {Rebecca A.} and Platt, {Frances M.} and Ulrich Schotten and Sander Verheule and Burton, {Rebecca A.B.}",
note = "Funding Information: R.A.B.B. is funded by a Sir Henry Dale Wellcome Trust and Royal Society Fellowship (109371/Z/15/Z) and R.A.B.B. acknowledges support from The Returning Carers\u2019 Fund (Oxford University, Medical Sciences Division). T.A. acknowledges the Global Challenges Research Fund, University of Oxford. R.A.B.B. is a Senior Research Fellow of at Linacre College. R.A.B.B. acknowledges research funds from the Ellis T Davies Fellowship Endowment, University of Liverpool. S.J.B. is funded by the British Heart Foundation. R.A.C. is funded by the Wellcome Trust and Royal Society. F.M.P. is a Wellcome Trust Investigator in Science and a Royal Society Wolfson merit award holder. D.A.P. was funded by the Mizutani Foundation. A.G. is a Wellcome Trust Senior Investigator and a Principal Investigator of the British Heart Foundation Center of Research Excellence at the University of Oxford. G.M. is a Wellcome Trust Senior Research Fellow. N.H. is a British Heart Foundation Senior Clinical Research Fellow (FS/SCRF/20/32005). We would like to thank the Galione, Parrington, and Tammaro Groups, Department of Pharmacology, University of Oxford for access to scientific equipment. We thank Dr Errin Johnson and Raman Dhaliwal from the Dunn School of Pathology for Electron Microscopy technical support. The goat model work was supported by the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hypercoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF, and Grant number 01-002-2022-0118, EmbRACE: Electro-Molecular Basis and the theRapeutic management of Atrial Cardiomyopathy, fibrillation and associated outcomEs), the European Union (CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, grant number 633196; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286). This research was funded in whole, or in part, by the Wellcome Trust [109371/Z/15/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. R.A.B.B. conceived and designed the study; S.V. and U.S. performed the goat AF experiments and provided the tissue for this study. T.A. G.B. R.F. and H.K. performed LC-MS/MS; T.A. and B.B. performed western blots; T.A. and D.P. performed enzyme assays; R.A.B.B. T.A. R.A.C. S.J.B. and F.P. contributed intellectually to the project and R.A.B.B. T.A. and S.J.B. drafted the paper. T.A. performed statistical analysis of proteomics and pathways analysis. A.P.C. and T.A. performed statistical analysis, on transcriptomics. P.D.C. performed integrated analysis of proteomics versus transcriptomics. S.J.B. performed the species comparison study. R.A.C. D.A. Q.S. and K.A. analyzed EM data. Q.S. G.R.M. and K.A. performed the manual and automated glycogen counts. T.A. created the figures related to proteomics. T.A. and A.P.C. created figures related to transcriptomics. P.D.C. and T.A. created integrated proteomics and transcriptomics analysis figures. G.R.M. created code for analyzing EM images for glycogen. B.B. performed western blotting studies on LC3 and p-p70. N.H. F.M.P. and A.G. contributed intellectually and provided technical access to equipment for this study. L.H. contributed intellectually relating to metabolism aspects of this study. All authors contributed to writing of the paper. The authors declare no competing interests. Funding Information: R.A.B.B. is funded by a Sir Henry Dale Wellcome Trust and Royal Society Fellowship (109371/Z/15/Z) and R.A.B.B. acknowledges support from The Returning Carers\u2019 Fund ( Oxford University , Medical Sciences Division). T.A. acknowledges the Global Challenges Research Fund, University of Oxford . R.A.B.B. is a Senior Research Fellow of at Linacre College. R.A.B.B. acknowledges research funds from the Ellis T Davies Fellowship Endowment, University of Liverpool . S.J.B. is funded by the British Heart Foundation . R.A.C. is funded by the Wellcome Trust and Royal Society . F.M.P. is a Wellcome Trust Investigator in Science and a Royal Society Wolfson merit award holder. D.A.P. was funded by the Mizutani Foundation . A.G. is a Wellcome Trust Senior Investigator and a Principal Investigator of the British Heart Foundation Center of Research Excellence at the University of Oxford. G.M. is a Wellcome Trust Senior Research Fellow. N.H. is a British Heart Foundation Senior Clinical Research Fellow (FS/SCRF/20/32005). We would like to thank the Galione, Parrington, and Tammaro Groups, Department of Pharmacology, University of Oxford for access to scientific equipment. We thank Dr Errin Johnson and Raman Dhaliwal from the Dunn School of Pathology for Electron Microscopy technical support. The goat model work was supported by the Netherlands Heart Foundation ( CVON2014-09 , RACE V Reappraisal of Atrial Fibrillation: Interaction between hypercoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF, and Grant number 01-002-2022-0118 , EmbRACE: Electro-Molecular Basis and the theRapeutic management of Atrial Cardiomyopathy, fibrillation and associated outcomEs), the European Union (CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, grant number 633196 ; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286 ). Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
month = jun,
day = "21",
doi = "10.1016/j.isci.2024.109609",
language = "English",
volume = "27",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "6",
}