Modulating the pro-apoptotic activity of cytochrome c at a biomimetic electrified interface

Abstract

Programmed cell death via apoptosis is a natural defence against excessive cell division, crucial for foetal development to maintenance of homeostasis and elimination of precancerous and senescent cells. Here we demonstrate an electrified liquid bio-interface that replicates the molecular machinery of the inner mitochondrial membrane at the onset of apoptosis. By mimicking in vivo cytochrome c (Cyt c) interactions with cell membranes, our platform allows us to modulate the conformational plasticity of the protein by simply varying the electrochemical environment at an aqueous|organic interface. Remarkably, we observe interfacial electron transfer between an organic electron donor decamethylferrocene and O2, electrocatalysed by Cyt c. This interfacial reaction requires partial Cyt c unfolding, mimicking Cyt c in vivo peroxidase activity. As proof-of-concept, we use our electrified liquid bio-interface to identify drug molecules, such as bifonazole, that can potentially downregulate Cyt c and protect against uncontrolled neuronal cell death in neurodegenerative disorders. ; D.T. thanks Science Foundation Ireland (SFI) for computing resources at the SFI/Higher Education Authority Irish Center for High-End Computing (ICHEC). A.G.-Q. acknowledges funding received from an Irish Research Council (IRC) Government of Ireland Postdoctoral Fellowship Award (Grant Number GOIPD/2018/252). G.H. and M.D. are grateful to the French Programme Investissement d'Avenir (PIA) "Lorraine Université d'Excellence" (Reference no. ANR-15-IDEX-04-LUE). M.D.S. and G.H. are grateful to the support of the IRC and Campus France for travel support between the French and Irish groups through their joint ULYSSES programme. DT thanks Science Foundation Ireland (SFI) for support (awards Grant Numbers 15/CDA/3491 and 12/RC/2275_P2).