Reductive stress, caused by an excess of antioxidants, is linked with several pathological conditions, including cancer and neurodegenerative diseases. However, the effects of reductive stress on cellular physiology remain poorly characterized. Using the nematode model Caenorhabditis elegans, we show that thiol antioxidants such as dithiothreitol (DTT) and β-mercaptoethanol modulate the methionine–homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase, rips-1. We carried out genetic screens to understand how thiol antioxidants resulted in the upregulation of rips-1. We discover that rips-1 is highly upregulated in mutants that have constitutive activation of the hypoxia response pathway. On the other hand, thiol antioxidants-mediated upregulation of rips-1 is fully blocked in mutants defective in hypoxia response. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol stress is conserved in human cells. The hypoxia response pathway enhances thiol toxicity via rips-1 expression and confers protection against thiol toxicity via rips-1-independent mechanisms. Finally, we show that DTT might activate the hypoxia response pathway by producing hydrogen sulfide. Our studies reveal an intriguing interaction between thiol-mediated reductive stress and the hypoxia response pathway.
About the Speaker:
Dr. Jogender Singh did his Ph.D. at the National Centre for Biological Sciences (NCBS), TIFR, Bengaluru, in 2015, and his postdoctoral research at Duke University, Durham, NC, USA, and the Oregon Health and Science University (OHSU), Portland, OR, USA. Subsequently, in January 2020, he joined the Department of Biological Sciences at IISER Bhopal as an assistant professor. He moved to the Department of Biological Sciences at IISER Mohali at the end of December 2020, where he currently serves as an assistant professor. His laboratory uses the model nematode C. elegans to understand cellular stress responses and their role in maintaining organismal homeostasis. He has been awarded the Ramalingaswami Re-entry Fellowship and the Har-Gobind Khorana Innovative Young Biotechnologist Fellowship from the Department of Biotechnology (DBT), India. He is an associate of the Indian Academy of Sciences, Bengaluru.