MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer

Jae Ho Seo, Young Chan Chae, Andrew V Kossenkov, Yu Geon Lee, Hsin-Yao Tang, Ekta Agarwal, Dmitry I Gabrilovich, Lucia R Languino, David W Speicher, Prashanth K Shastrula, Alessandra Maria Storaci, Stefano Ferrero, Gabriella Gaudioso, Manuela Caroli, Davide Tosi, Massimo Giroda, Valentina Vaira, Vito W Rebecca, Meenhard Herlyn, Min XiaoDylan Fingerman, Alessandra Martorella, Emmanuel Skordalakes, Dario C Altieri

Research output: Contribution to journalArticlepeer-review

Abstract

The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of mitochondrial fission factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, that is, mitochondrial dynamics, were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex, acutely depolarized mitochondria, and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, and glioblastoma neurospheres. These data identify the MFF-VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer. SIGNIFICANCE: These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF-VDAC complex and displays anticancer activity in multiple tumor models.See related commentary by Rao, p. 6074.

Original languageEnglish
Pages (from-to)6215-6226
Number of pages12
JournalCancer Research
Volume79
Issue number24
DOIs
Publication statusPublished - Dec 15 2019

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