Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer

Jae Ho Seo, Ekta Agarwal, Young Chan Chae, Yu Geon Lee, David S. Garlick, Alessandra Maria Storaci, Stefano Ferrero, Gabriella Gaudioso, Umberto Gianelli, Valentina Vaira, Dario C. Altieri

Research output: Contribution to journalArticle

Abstract

Background: Mitochondrial functions are exploited in cancer and provide a validated therapeutic target. However, how this process is regulated has remained mostly elusive and the identification of new pathways that control mitochondrial integrity in cancer is an urgent priority. Methods: We studied clinically-annotated patient series of primary and metastatic prostate cancer, representative cases of multiple myeloma (MM) and publicly available genetic databases. Gene regulation studies involved chromatin immunoprecipitation, PCR amplification and Western blotting of conditional Myc-expressing cell lines. Transient or stable gene silencing was used to quantify mitochondrial functions in bioenergetics, outer membrane permeability, Ca2+ homeostasis, redox balance and cell death. Tumorigenicity was assessed by cell proliferation, colony formation and xenograft tumour growth. Findings: We identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancer, compared to normal tissues. Biochemically, MFF isoforms, MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel-1 (VDAC1) at the mitochondrial outer membrane, in vivo. Disruption of this complex by MFF silencing induces general collapse of mitochondrial functions with increased outer membrane permeability, loss of inner membrane potential, Ca2+ unbalance, bioenergetics defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice. Interpretation: An MFF-VDAC1 complex is a novel regulator of mitochondrial integrity and actionable therapeutic target in cancer.

Original languageEnglish
Pages (from-to)353-363
Number of pages11
JournalEBioMedicine
Volume48
DOIs
Publication statusPublished - Oct 1 2019

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Mitochondrial Dynamics
Voltage-Dependent Anion Channel 1
Permeability
Membranes
Tumors
Cell proliferation
Cell death
Heterografts
Neoplasms
Energy Metabolism
Gene expression
Cell Death
Chromatin
Amplification
Cell Proliferation
Protein Isoforms
Genes
Genetic Databases
Chemical activation
Cells

Keywords

  • Cancer therapy
  • Cell death
  • MFF
  • Mitochondria
  • Tumour metabolism
  • VDAC1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Seo, J. H., Agarwal, E., Chae, Y. C., Lee, Y. G., Garlick, D. S., Storaci, A. M., ... Altieri, D. C. (2019). Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. EBioMedicine, 48, 353-363. https://doi.org/10.1016/j.ebiom.2019.09.017

Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. / Seo, Jae Ho; Agarwal, Ekta; Chae, Young Chan; Lee, Yu Geon; Garlick, David S.; Storaci, Alessandra Maria; Ferrero, Stefano; Gaudioso, Gabriella; Gianelli, Umberto; Vaira, Valentina; Altieri, Dario C.

In: EBioMedicine, Vol. 48, 01.10.2019, p. 353-363.

Research output: Contribution to journalArticle

Seo, Jae Ho ; Agarwal, Ekta ; Chae, Young Chan ; Lee, Yu Geon ; Garlick, David S. ; Storaci, Alessandra Maria ; Ferrero, Stefano ; Gaudioso, Gabriella ; Gianelli, Umberto ; Vaira, Valentina ; Altieri, Dario C. / Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. In: EBioMedicine. 2019 ; Vol. 48. pp. 353-363.
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AU - Garlick, David S.

AU - Storaci, Alessandra Maria

AU - Ferrero, Stefano

AU - Gaudioso, Gabriella

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