Extracellular Electron Transfer Mediated by a Cytocompatible Redox Polymer Lengthens the Circadian Period of Mammalian Cells

The crosstalk among the circadian clock, cellular metabolism, and cellular redox state has attracted much attention. To elucidate this crosstalk, chemical compounds have been used to perturb cellular metabolism and the redox state. However, extracellular electron transfer (EET) with an electron mediator has not been used to study the mammalian circadian clock due to potential cytotoxic effects of the mediator. Here, we describe the use of EET mediated by pMFc, a cytocompatible redox polymer, on human U2OS cells. EET mediated by oxidized pMFc (ox-pMFc) extracted intracellular electrons, resulting in a longer circadian period. Analyses of the metabolome and intracellular redox species suggest that ox-pMFc receives an electron from glutathione, thereby inducing pentose phosphate pathway activation. We anticipate that redox perturbation via EET will provide new insights into the crosstalk among the circadian clock, metabolism, and redox state, which may lead to the development of new treatments for circadian clock disorders.