m3,4-Dihydroxyphenylglycol, a major catecholamine metabolite in the brain, prevents ferroptotic cell injury via covalent inhibition of protein disulfide isomerase.

Abstract

Ferroptosis, a regulated form of oxidative cell death often resulting from cellular glutathione depletion, has been implicated in the etiology of many human diseases. Our recent studies have shown that protein disulfide isomerase (PDI or PDIA1) is a mediator of ferroptosis and thus also a target for cytoprotection. Here, we report that 3,4-dihydroxyphenylglycol (DHPG), a major catecholamine metabolite in the brain, can strongly suppress oxidative cell death in neurons as well as in other cells in culture challenged with commonly-used ferroptosis inducers, including erastin, RSL3, FINO2 and sulfasalazine. Mechanistic investigations reveal that DHPG can directly bind to PDI in live neuronal cells (cellular thermal shift assay), covalently modify PDI's active site thiol residues (mass spectrometry analysis), and inhibit PDI's catalytic activity (enzymatic assay). In erastin- or RSL3-exposed neuronal cells, DHPG can inhibit PDI oxidase-mediated NOS dimerization (i.e., catalytic activation), which is followed by reduced accumulation of cellular nitric oxide and reactive oxygen species, and ultimately, protection against ferroptosis. siRNA-mediated PDI knockdown significantly suppresses NOS and nitric oxide accumulation, and attenuates the protective effect of DHPG. Collectively, these observations reveal, for the first time, that DHPG, a major catecholamine metabolite in the brain, has the ability to effectively prevent ferroptotic injury in neurons and other cells via inhibition of the PDI - NOS - NO signaling axis.

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