Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation
Thamali Ayagama,
Philip D. Charles,
Samuel J. Bose,
Barry Boland,
David A. Priestman,
Daniel Aston,
Georgina Berridge,
Roman Fischer,
Adam P. Cribbs,
Qianqian Song,
Gary R. Mirams,
Kwabena Amponsah,
Lisa Heather,
Antony Galione,
Neil Herring,
Holger Kramer,
Rebecca A. Capel,
Frances M. Platt,
Ulrich Schotten,
Sander Verheule,
Rebecca A.B. Burton
Affiliations
Thamali Ayagama
Department of Pharmacology, University of Oxford, Oxford, UK
Philip D. Charles
Target Discovery Institute, University of Oxford, Oxford, UK
Samuel J. Bose
Department of Pharmacology, University of Oxford, Oxford, UK
Barry Boland
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
David A. Priestman
Department of Pharmacology, University of Oxford, Oxford, UK
Daniel Aston
Department of Anaesthesia and Critical Care, Royal Papworth Hospital NHS Foundation Trust, Papworth Road, Cambridge CB2 0AY, UK
Georgina Berridge
Target Discovery Institute, University of Oxford, Oxford, UK
Roman Fischer
Target Discovery Institute, University of Oxford, Oxford, UK
Adam P. Cribbs
Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Headington OX3 7LD, UK
Qianqian Song
Department of Pharmacology, University of Oxford, Oxford, UK
Gary R. Mirams
Centre for Mathematical Medicine & Biology, Mathematical Sciences, University of Nottingham, Nottingham NG7 2RD, UK
Kwabena Amponsah
Centre for Mathematical Medicine & Biology, Mathematical Sciences, University of Nottingham, Nottingham NG7 2RD, UK
Lisa Heather
Department of Physiology, Anatomy and Genetics, , University of Oxford, South Park Road, Oxford OX1 3PT, UK
Antony Galione
Department of Pharmacology, University of Oxford, Oxford, UK
Neil Herring
Department of Physiology, Anatomy and Genetics, , University of Oxford, South Park Road, Oxford OX1 3PT, UK
Holger Kramer
Mass spectrometry Facility, The MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
Rebecca A. Capel
Department of Pharmacology, University of Oxford, Oxford, UK
Frances M. Platt
Department of Pharmacology, University of Oxford, Oxford, UK
Ulrich Schotten
Departments of Physiology and Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Sander Verheule
Departments of Physiology and Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Rebecca A.B. Burton
Department of Pharmacology, University of Oxford, Oxford, UK; University of Liverpool, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, Liverpool, UK; Corresponding author
Summary: 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.
