Mitochondrial C3aR and endoplasmic reticulum C5aR orchestrate calcium imbalance during oxidative stress in retinal...

Although C3a and C5a are classically recognized as extracellular anaphylatoxins, we previously identified mitochondrial C3a receptors (mt-C3aR) in stressed RPE cells, where its activation enhanced Ca²⁺ uptake and inhibited oxidative phosphorylation (OXPHOS). Here, we demonstrate a second intracellular anaphylatoxin receptor, C5aR, localized to the endoplasmic reticulum (ER) by confocal and immuno-electron microscopy. ER-C5aR activation increased SERCA-dependent Ca²⁺ uptake and, together with mt-C3aR, facilitated ER-to-mitochondria Ca²⁺ transfer at mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, oxidative stress induced Gα16 redistribution, enabling its interaction with ER-C5aR. These findings reveal a novel mechanism by which intracellular anaphylatoxin receptors shape Ca²⁺ homeostasis and cellular stress responses.