Microtubule-Dependent Mitochondria Alignment Regulates Calcium Release in Response to Nanomechanical Stimulus in Heart Myocytes

• Published in: Cell reports (Cambridge) 2016-01, Vol.14 (1), p.140-151
• Main Authors: Miragoli, Michele, Sanchez-Alonso, Jose L., Bhargava, Anamika, Wright, Peter T., Sikkel, Markus, Schobesberger, Sophie, Diakonov, Ivan, Novak, Pavel, Castaldi, Alessandra, Cattaneo, Paola, Lyon, Alexander R., Lab, Max J., Gorelik, Julia
• Format: Article
• Language: English
• Subjects: Calcium - metabolism; Calcium Signaling; Cells, Cultured; Heart Failure - metabolism; Heart Failure - pathology; Humans; Mechanotransduction, Cellular; Microtubules - metabolism; Microtubules - pathology; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.12.014

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. [Display omitted] •Nanomechanical pressure application changes mechanosensitivity in failing heart cells•Microtubular network disorganization mediates the change in mechanosensitivity•Mitochondria are displaced from their original location and trigger calcium release•Uncoupling the mitochondrial proton gradient completely abolishes the phenomena Miragoli et al. show that failing heart cells have altered sensitivity to nanomechanical stimuli mediated by changes in the alignment of microtubules. The microtubule network disorganization leads to displacement of mitochondria and alterations in calcium release.