1. Peptides Targeting the IF1–ATP Synthase Complex Modulate the Permeability Transition Pore in Cancer HeLa Cells
- Author
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Martina Grandi, Simone Fabbian, Giancarlo Solaini, Alessandra Baracca, Massimo Bellanda, and Valentina Giorgio
- Subjects
cancer ,mitochondria ,therapy ,ATP synthase ,permeability transition pore ,inhibitor protein IF1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The mitochondrial protein IF1 is upregulated in many tumors and acts as a pro-oncogenic protein through its interaction with the ATP synthase and the inhibition of apoptosis. We have recently characterized the molecular nature of the IF1–Oligomycin Sensitivity Conferring Protein (OSCP) subunit interaction; however, it remains to be determined whether this interaction could be targeted for novel anti-cancer therapeutic intervention. We generated mitochondria-targeting peptides to displace IF1 from the OSCP interaction. The use of one selective peptide led to displacement of the inhibitor IF1 from ATP synthase, as shown by immunoprecipitation. NMR spectroscopy analysis, aimed at clarifying whether these peptides were able to directly bind to the OSCP protein, identified a second peptide which showed affinity for the N-terminal region of this subunit overlapping the IF1 binding region. In situ treatment with the membrane-permeable derivatives of these peptides in HeLa cells, that are silenced for the IF1 inhibitor protein, showed significant inhibition in mitochondrial permeability transition and no effects on mitochondrial respiration. These peptides mimic the effects of the IF1 inhibitor protein in cancer HeLa cells and confirm that the IF1–OSCP interaction inhibits apoptosis. A third peptide was identified which counteracts the anti-apoptotic role of IF1, showing that OSCP is a promising target for anti-cancer therapies.
- Published
- 2024
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