Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments.
Actin Cytoskeleton
/ metabolism
Actins
/ metabolism
Adenocarcinoma of Lung
/ genetics
Animals
Carrier Proteins
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Cell Survival
/ genetics
DNA, Mitochondrial
/ metabolism
Electron Transport Complex I
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Gene Knockout Techniques
Humans
Lung Neoplasms
/ genetics
Male
Metabolomics
Mice
Mice, Nude
Microfilament Proteins
/ genetics
Mitochondria
/ genetics
Oxidative Phosphorylation
Proteomics
RNA Interference
Saccharomyces cerevisiae Proteins
/ genetics
Transplantation, Heterologous
NSCLC
OXPHOS
actin
fascin
metastasis
metastatic colonization
mitochondria
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
10 09 2019
10 09 2019
Historique:
received:
29
01
2019
revised:
24
06
2019
accepted:
31
07
2019
entrez:
12
9
2019
pubmed:
12
9
2019
medline:
17
9
2020
Statut:
ppublish
Résumé
The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence.
Identifiants
pubmed: 31509745
pii: S2211-1247(19)31044-7
doi: 10.1016/j.celrep.2019.08.011
pmc: PMC6759858
mid: NIHMS1539603
pii:
doi:
Substances chimiques
Actins
0
Carrier Proteins
0
DNA, Mitochondrial
0
FSCN1 protein, human
0
Microfilament Proteins
0
Ndi1 protein, S cerevisiae
0
Saccharomyces cerevisiae Proteins
0
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2824-2836.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA216853
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163649
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210439
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233844
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA175741
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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