title: Microtubule-Dependent Mitochondria Alignment Regulates Calcium Release in Response to Nanomechanical Stimulus in Heart Myocytes.
abstract: Arrhythmogenesis during heart failure is a major clinical problem. Regional electrical gradients produce arrhythmias, and cellular ionic transmembrane gradients are its originators. We investigated whether the nanoscale mechanosensitive properties of cardiomyocytes from failing hearts have a bearing upon the initiation of abnormal electrical activity. Hydrojets through a nanopipette indent specific locations on the sarcolemma and initiate intracellular calcium release in both healthy and heart failure cardiomyocytes, as well as in human failing cardiomyocytes. In healthy cells, calcium is locally confined, whereas in failing cardiomyocytes, calcium propagates. Heart failure progressively stiffens the membrane and displaces sub-sarcolemmal mitochondria. Colchicine in healthy cells mimics the failing condition by stiffening the cells, disrupting microtubules, shifting mitochondria, and causing calcium release. Uncoupling the mitochondrial proton gradient abolished calcium initiation in both failing and colchicine-treated cells. We propose the disruption of microtubule-dependent mitochondrial mechanosensor microdomains as a mechanism for abnormal calcium release in failing heart.
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK; Humanitas Clinical and Research Center, via Manzoni 56, Rozzano, 20090 Milan, Italy; Center of Excellence for Toxicological Research, INAIL exISPESL, University of Parma, via Gramsci 14, 43126 Parma, Italy. Electronic address: michele.miragoli@humanitasresearch.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Miragoli
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sanchez-Alonso
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK; Department of Biotechnology, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram, 502205 Telangana, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Wright
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Sikkel
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schobesberger
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Diakonov
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Pavel
authors.initials: P
authors.lastname: Novak
authors.affiliation: Humanitas Clinical and Research Center, via Manzoni 56, Rozzano, 20090 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castaldi
authors.affiliation: Humanitas Clinical and Research Center, via Manzoni 56, Rozzano, 20090 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cattaneo
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London SW36NP, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK. Electronic address: m.lab@imperial.ac.uk.
authors.forename: Max J
authors.initials: MJ
authors.lastname: Lab
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus Du Cane Road, London W12 0NN, UK. Electronic address: j.gorelik@imperial.ac.uk.
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D040542:Mechanotransduction, Cellular; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
chemical_list: D002118:Calcium