Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle
Open Access
- 10 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (8), 2383-2401
- https://doi.org/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.Keywords
Funding Information
- Ministero della Salute (GR-2011-02350544, Ricerca corrente 2017)
- Ministero dell'Istruzione, dell'Università e della Ricerca (2015MJBEM2, 2017FJSM9S)
- Ministero dell'Istruzione, dell'Università e della Ricerca
This publication has 56 references indexed in Scilit:
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Nitric Oxide Sustains Long-Term Skeletal Muscle Regeneration by Regulating Fate of Satellite Cells Via Signaling Pathways Requiring Vangl2 and Cyclic GMPThe International Journal of Cell Cloning, 2012
- Mitochondrial shape changes: orchestrating cell pathophysiologyEMBO Reports, 2010
- Nitric oxide inhibition of Drp1-mediated mitochondrial fission is critical for myogenic differentiationCell Death & Differentiation, 2010
- Kinesin superfamily motor proteins and intracellular transportNature Reviews Molecular Cell Biology, 2009
- Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial FissionOnline Journal of Public Health Informatics, 2009
- Bidirectional Ca 2+ -dependent control of mitochondrial dynamics by the Miro GTPaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondriaProceedings of the National Academy of Sciences of the United States of America, 2008
- Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independentThe Journal of cell biology, 2006
- Molecular motors and mechanisms of directional transport in neuronsNature Reviews Neuroscience, 2005