title: Antiferroptotic activity of non-oxidative dopamine.
abstract: Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters.
authors: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Ding
authors: D
authors: Wang
authors: The Third Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Yingpeng
authors: Y
authors: Peng
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Yangchun
authors: Y
authors: Xie
authors: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Borong
authors: B
authors: Zhou
authors: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Xiaofang
authors: X
authors: Sun
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Rui
authors: R
authors: Kang
authors: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: tangd2@upmc.edu.
authors: Daolin
authors: D
authors: Tang
mesh_terms: D016923:Cell Death / Q000187:drug effects* / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction
chemical_list: D007501:Iron; D004298:Dopamine
keywords: Dopamine; Ferroptosis; Iron; Lipid peroxidation; Receptor