Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments

Shengchen Lin, Chongbiao Huang, Venugopal Gunda, Jianwei Sun, Srikumar P. Chellappan, Zengxun Li, Victoria Izumi, Bin Fang, John Koomen, Pankaj K. Singh, Jihui Hao, Shengyu Yang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2824-2836.e8
JournalCell Reports
Volume28
Issue number11
DOIs
StatePublished - Sep 10 2019

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Oxidative Phosphorylation
Actin Cytoskeleton
Actins
Lung Neoplasms
Physiological Stress
Neoplasm Metastasis
Electron Transport Complex I
Metabolomics
Mitochondrial DNA
Proteomics
fascin
Mitochondria
Respiration
Homeostasis
Deregulation
Yeasts
Metabolism
Recurrence
Yeast
Lung

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lin, Shengchen ; Huang, Chongbiao ; Gunda, Venugopal ; Sun, Jianwei ; Chellappan, Srikumar P. ; Li, Zengxun ; Izumi, Victoria ; Fang, Bin ; Koomen, John ; Singh, Pankaj K. ; Hao, Jihui ; Yang, Shengyu. / Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments. In: Cell Reports. 2019 ; Vol. 28, No. 11. pp. 2824-2836.e8.
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Lin, S, Huang, C, Gunda, V, Sun, J, Chellappan, SP, Li, Z, Izumi, V, Fang, B, Koomen, J, Singh, PK, Hao, J & Yang, S 2019, 'Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments', Cell Reports, vol. 28, no. 11, pp. 2824-2836.e8. https://doi.org/10.1016/j.celrep.2019.08.011

Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments. / Lin, Shengchen; Huang, Chongbiao; Gunda, Venugopal; Sun, Jianwei; Chellappan, Srikumar P.; Li, Zengxun; Izumi, Victoria; Fang, Bin; Koomen, John; Singh, Pankaj K.; Hao, Jihui; Yang, Shengyu.

In: Cell Reports, Vol. 28, No. 11, 10.09.2019, p. 2824-2836.e8.

Research output: Contribution to journalArticle

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AU - Lin, Shengchen

AU - Huang, Chongbiao

AU - Gunda, Venugopal

AU - Sun, Jianwei

AU - Chellappan, Srikumar P.

AU - Li, Zengxun

AU - Izumi, Victoria

AU - Fang, Bin

AU - Koomen, John

AU - Singh, Pankaj K.

AU - Hao, Jihui

AU - Yang, Shengyu

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N2 - 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.

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