Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle
Open accessAbstract
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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Mitochondrial fission is essential for skeletal muscle health.
“Taken altogether, the findings discussed above clearly indicate that mitochondrial fission is essential for skeletal muscle health.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [40]
Muscle-specific Drp1 overexpression impairs skeletal muscle growth in mice.
“Muscle-specific Drp1 overexpression was shown to impair skeletal muscle growth in mice [39,40].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [40]
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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
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2020-02-10
- Volume
- 27
- Issue
- 8
- Pages
- 2383-2401
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC7370230
- 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
- hybrid
- doi.org
- 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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