Mitochondrial C3aR and endoplasmic reticulum C5aR orchestrate calcium imbalance during oxidative stress in retinal pigment epithelial cells

Mitochondrion. 2026 Jun 3:102172. doi: 10.1016/j.mito.2026.102172. Online ahead of print.

ABSTRACT

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.

PMID:42242609 | DOI:10.1016/j.mito.2026.102172