* 일시: 5/19(목) 16:30
* 연사: 서재호 (원광대학교)
* 장소: 벤처관 711호
* 링크: https://ssu-ac-kr.zoom.us/meeting/register/tZ0tce2grzMiGtRxC27Q0ciS7jWTKo0Etequ
* 제목: Mitochondria-targeted cancer therapy: MFF regulation of mitochondrial cell death and its application
Mitochondria control many forms of cell death, such as necrosis and apoptosis through the activity of a permeability transition pore (PTP). The composition of the PTP is still a matter of debate, and its regulators have remained mostly elusive, but PTP functions are exploited in disease, such as cancer, and provide a therapeutic target. Here, we show that protein isoforms of Mitochondrial Fission Factor (MFF), a molecule previously implicated in the control of mitochondrial size and shape, i.e. mitochondrial dynamics, are highly expressed in patients with primary and metastatic prostate cancer, compared to normal tissues. MFF1 and MFF2 form homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability, inserting 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 feasible, triggers acute mitochondrial permeability transition in tumor but not normal cells, and delivers potent cytotoxic activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, glioblastoma neurospheres and patient-derived drugs (Dabrafenib/Trametinib)-resistant melanoma. These data identify the MFF–VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer.