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Title: | Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle | Authors: | Giovarelli, Matteo Zecchini, Silvia Martini, Emanuele Garrè, Massimiliano Barozzi, Sara Ripolone, Michela Napoli, Laura Coazzoli, Marco Vantaggiato, Chiara Roux-Biejat, Paulina Cervia, Davide Moscheni, Claudia Perrotta, Cristiana Parazzoli, Dario Clementi, Emilio De Palma, Clara |
Journal: | CELL DEATH AND DIFFERENTIATION | Issue Date: | 2020 | Abstract: | Mitochondria change distribution across cells following a variety of pathophysiological stimuli. The mechanisms presiding over this redistribution are yet undefined. In a murine model overexpressing Drp1 specifically in skeletal muscle, we find marked mitochondria repositioning in muscle fibres and we demonstrate that Drp1 is involved in this process. Drp1 binds KLC1 and enhances microtubule-dependent transport of mitochondria. Drp1-KLC1 coupling triggers the displacement of KIF5B from kinesin-1 complex increasing its binding to microtubule tracks and mitochondrial transport. High levels of Drp1 exacerbate this mechanism leading to the repositioning of mitochondria closer to nuclei. The reduction of Drp1 levels decreases kinesin-1 activation and induces the partial recovery of mitochondrial distribution. Drp1 overexpression is also associated with higher cyclin-dependent kinase-1 (Cdk-1) activation that promotes the persistent phosphorylation of desmin at Ser-31 and its disassembling. Fission inhibition has a positive effect on desmin Ser-31 phosphorylation, regardless of Cdk-1 activation, suggesting that induction of both fission and Cdk-1 are required for desmin collapse. This altered desmin architecture impairs mechanotransduction and compromises mitochondrial network stability priming mitochondria transport through microtubule-dependent trafficking with a mechanism that involves the Drp1-dependent regulation of kinesin-1 complex. |
URI: | http://hdl.handle.net/2067/43495 | ISSN: | 1476-5403 | DOI: | 10.1038/s41418-020-0510-7 | Rights: | Attribution-NonCommercial-NoDerivs 3.0 United States |
Appears in Collections: | A1. Articolo in rivista |
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Giovarelli et al Cell Death Diff 2020.pdf | 7.77 MB | Adobe PDF | Request a copy |
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