Cited by 41Mitochondrial Function and PathologyMuscle Physiology and DisordersAutophagy in Disease and Therapy

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

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Giovarelli, Matteo, Zecchini, Silvia, Martini, Emanuele, Garrè, Massimiliano, Barozzi, Sara, Ripolone, Michela, Napoli, Laura, Coazzoli, Marco +8 more·2020·Cell Death & Differentiation

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.

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Authors
Giovarelli, M., Zecchini, S., Martini, E., Garrè, M., Barozzi, S., Ripolone, M., Napoli, L., Coazzoli, M., Vantaggiato, C., Roux-Biejat, P., Cervia, D., Moscheni, C., Perrotta, C., Parazzoli, D., Clementi, E., & De Palma, C.
Affiliations
  • University of Milan (IT)
  • IFOM (IT)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
  • IRCCS Eugenio Medea (IT)
  • Università degli Studi della Tuscia (IT)
Corresponding author
Clementi, Emilio
Venue
Cell Death & Differentiation
Published
2020-02-10
Volume
27
Issue
8
Pages
2383-2401
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
OpenAlex
W3005263809
Cited by
41
References
58
Citations by year
2026: 2 · 2025: 5 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 9
FWCI
2.27
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • UnitusOpen (Tuscia University) (submittedVersion, cc-by)
  • UnitusOpen (Tuscia University) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by)
Funders
  • Ministero della Salute (GR-2011-02350544, Ricerca corrente 2017)
  • Ministero dell'Istruzione, dell'Università e della Ricerca (2015MJBEM2, 2017FJSM9S)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Drp1, mitochondrial fission, mitochondrial trafficking, kinesin-1, KLC1, KIF5B, CDK1, microtubule transport, skeletal muscle, mechanotransduction
MeSH terms
Animals, Desmin, Enzyme Activation, Humans, Mice, Inbred C57BL, Microtubules, Mitochondria, Phosphorylation, Phosphoserine, Succinate Dehydrogenase, CDC2 Protein Kinase, Kinesins, Muscle, Skeletal, Protein Transport, Dynamins, Quinazolinones

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