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

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.