YT521-B homology domain containing 1 ameliorates mitochondrial damage and ferroptosis in sleep deprivation by activating the sirtuin 1/nuclear factor erythroid-derived 2-like 2/heme oxygenase 1 pathway

Abstract

In sleep deprivation (SD) models, ferroptosis is increased. SIRT1 alleviates cognitive impairment in SD, and SIRT1/NRF2/HO1 pathway depresses ferroptosis in different diseases. Moreover, YTHDC1 can regulate SIRT1 mRNA stability. Therefore, our study explored effects of the YTHDC1/SIRT1/NRF2/HO1 axis on neuronal damage and ferroptosis in SD. The SD mouse model was established through a modified multi-platform water environment method and a cell model of ferroptosis was constructed with Erastin, followed by gain- and loss-of-function assays. In mice, the cognitive impairment and CLOCK and BMAL1 levels in hippocampal tissues were assessed. In cells, viability was measured. In mice and cells, mitochondrial ultrastructure, the content of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and iron, and the expression of GPX4 and ACSL4 were detected. The potential relationships among YTHDC1, SIRT1, and NRF2 were analyzed. SD mice had downregulated YTHDC1, SIRT1, NRF2, and HO1 protein expression in hippocampal tissues and increased ferroptosis. Mechanically, SIRT1 activated the NRF2/HO1 pathway through deacetylation, and YTHDC1 increased SIRT1 mRNA stability. YTHDC1 overexpression diminished mitochondrial damage, the content of ROS, iron, and MDA, and the expression of ACSL4 while enhancing GSH contents and GPX4 expression in hippocampal tissues of SD mice and Erastin-induced HT22 cells. Additionally, YTHDC1 overexpression elevated viability in Erastin-induced HT22 cells. SIRT1 or NRF2 overexpression ameliorated Erastin-induced mitochondrial damage and ferroptosis in HT22 cells. Silencing SIRT1 abolished the impact of YTHDC1 overexpression on SD mice and Erastin-induced HT22 cells. Collectively, YTHDC1 ameliorates mitochondrial damage and ferroptosis after SD by activating the SIRT1/NRF2/HO1 pathway.

Keywords: Deacetylation; Ferroptosis; Mitochondrial damage; NRF2/HO1; Nuclear localization; SIRT1; Sleep deprivation; YTHDC1.