8.A.166.  The Mitochondrial Fission Factor (MFF) Family

Seo et al. 2019 identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancers, 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, bioenergetic defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice. MFF1 and MFF2, which controls mitochondrial size and shape (i.e., mitochondrial dynamics) were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with VDAC1 (See TC# 1.B.8). MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites (Seo et al. 2019). A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex, 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. Thus, the MFF-VDAC1 complex is a regulator of mitochondrial cell death and an actionable therapeutic target in cancer (Rao 2019). Members of this family appear to derive exclusively from animals.

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