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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
Issue Date: 2020
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.
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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