Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle.
Animals
CDC2 Protein Kinase
/ metabolism
Desmin
/ metabolism
Dynamins
/ metabolism
Enzyme Activation
Humans
Kinesins
/ metabolism
Mice, Inbred C57BL
Microtubules
/ metabolism
Mitochondria
/ metabolism
Muscle, Skeletal
/ metabolism
Phosphorylation
Phosphoserine
/ metabolism
Protein Transport
Quinazolinones
/ metabolism
Succinate Dehydrogenase
/ metabolism
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
01
08
2019
accepted:
23
01
2020
revised:
13
12
2019
pubmed:
12
2
2020
medline:
24
9
2021
entrez:
12
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32042098
doi: 10.1038/s41418-020-0510-7
pii: 10.1038/s41418-020-0510-7
pmc: PMC7370230
doi:
Substances chimiques
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
0
Desmin
0
KLC1 protein, human
0
Kns2 protein, mouse
0
Quinazolinones
0
Phosphoserine
17885-08-4
Succinate Dehydrogenase
EC 1.3.99.1
CDC2 Protein Kinase
EC 2.7.11.22
Kinesins
EC 3.6.4.4
Dnm1l protein, mouse
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2383-2401Références
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