Hypoxia-driven calcium imbalance causes lysosomal dysfunction and alters macrophage proteolysis and host defense

ABSTRACT: Macrophages clear pathogens and cellular debris via lysosomal degradation. During inflammation, macrophages experience hypoxia, yet the dynamics and function of their organelles, including lysosomes, remains largely unknown under oxygen restriction. We addressed this knowledge gap and discovered that hypoxia triggers the formation of enlarged late endosomes/lysosomes which localize to the cell periphery in macrophages from various mammalian species. The degradation ability of macrophages, especially the activity of lysosomal cathepsins, was severely impaired under oxygen restriction. Defective proteolysis under hypoxia was due to lysosomal alkalization due to excessive calcium accumulation. This process was primarily controlled by the activation of the ryanodine receptors (RyR), a class of ER calcium transporters. These calcium-induced changes also altered cathepsin activity in mycobacteria-infected macrophages under hypoxic conditions. Although lysosomal cathepsins were essential for killing mycobacteria under oxygen restriction, RyR inhibition alone did not affect bacterial loads, despite partly restoring cathepsin activity. Our findings show that hypoxia alters lysosomal homeostasis via dysregulated calcium accumulation and these alterations directly impact on host proteolysis and responses to infection in macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308405 | GEO | 2026/09/01

REPOSITORIES: GEO