Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle

Matteo Giovarelli,Sara Barozzi,Laura Napoli,Chiara Vantaggiato,Cristiana Perrotta,Claudia Moscheni,Marco Coazzoli,Massimiliano Garrè,Michela Ripolone,Davide Cervia,Emanuele Martini,Silvia Zecchini,Paulina Roux-Biejat,Dario Parazzoli,Clara De Palma,Emilio Clementi

doi:10.1038/s41418-020-0510-7

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.

Highlights

Mitochondria play a key role in cellular homoeostasis and the proper regulation of mitochondrial transport ensuresThese authors contributed : Matteo Giovarelli, Silvia Zecchini Edited by L
dynamin-related protein 1 (Drp1) is more active in Drp/MC mice leading to progressive alterations of mitochondrial network
In Drp/MC transgenic mice we found a significant increase in Drp1 phosphorylation at Ser-616 combined with a decreased phosphorylation at Ser-637, indicating a hyperactivation of Drp1 (Fig. 1a)

Summary

Introduction

Mitochondria play a key role in cellular homoeostasis and the proper regulation of mitochondrial transport ensures. These authors contributed : Matteo Giovarelli, Silvia Zecchini Edited by L. Mitochondria use MT and intermediate filaments (IF) for their movement and proper localisation. IF do not provide directional transport [9] but arrest and anchor mitochondria in the specific cellular locations where they are required [10, 11]. Lack of desmin results in perturbations of mitochondrial positioning with subsarcolemmal aggregation of mitochondria [12]. The same occurs in the absence of IF–microfilament cross-linkers [11, 13, 14] supporting the evidence that IF alterations can change mitochondrial morphology and localisation

Methods

Results

Conclusion