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Publication : GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.

First Author  Zhao F Year  2024
Journal  Dev Cell PubMed ID  38981469
Mgi Jnum  J:352087 Mgi Id  MGI:7704971
Doi  10.1016/j.devcel.2024.06.007 Citation  Zhao F, et al. (2024) GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development. Dev Cell
abstractText  Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4(-)CD8(-) double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.
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