https://pubmed.ncbi.nlm.nih.gov/39341036/
Abstract: Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.
Funding: This research has been financed by grants from the Spanish Government (partially funded by the European Union ERDF “A way of making Europe” and Next GenerationEU): RedoxStroke (RTI2018- 094203-B-I00), excellence network RED2018-102576-T, NCLRedoX (PID2021-124688OB-I00), NCLXtroke (PDC2022-133246-I00),
PID2021-125986OB-I00 and PID2022-139936OA-I00 from AEI (MICIU/ AEI/10.13039/501100011033); PI15/00107, PI22/00362 and RICORSICTUS (RD21/0006/0009) from Instituto de Salud Carlos III (ISCIII) and fellowships IJC2020-042679-I (MICIU) and RYC2022-036516-I (MICIU) to P.H.-A. from AEI and FPU18/03475 to C.C.-F. from MICIU, and by a grant from the Fundacion ´ Domingo Martínez.