Chemerin-CMKLR1 differentially mediated OGD/R-induced mitochondrial dysfunction, oxidative stress, and autophagy in...

Ischemia-reperfusion (I/R) injury exacerbates tissue damage upon reperfusion after ischemia. The effects of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), on I/R injury remain poorly understood. We hypothesized that the chemerin-CMKLR1 axis differentially regulates signaling in microglia and neuronal cells during oxygen-glucose deprivation/reoxygenation (OGD/R), influencing mitochondrial function, oxidative stress, and autophagy. Using BV2 microglia and Neuro-2a (N2a) neuronal cells, we examined OGD/R-induced changes in the expression of the autophagy-associated proteins chemerin and CMKLR1. We investigated the functional consequences of CMKLR1 overexpression and chemerin treatment on oxidative stress, apoptosis, autophagy, and mitochondrial dynamics in BV2 microglia and N2a neuronal cells. Following OGD/R, CMKLR1 expression was downregulated, whereas autophagy was upregulated in both cell types. In contrast, chemerin expression decreased in BV2 microglia but increased in N2a cells. Treatment with chemerin dose-dependently reduced oxidative stress and apoptosis while enhancing mitochondrial fusion, suppressing fission, and promoting autophagy and mitochondrial function in both cell types under OGD/R conditions. CMKLR1 overexpression exacerbated mitochondrial respiratory dysfunction, mitochondrial fusion, fission, and increased autophagy (LC3II/LC3I and Pink1 levels), with cell type-specific differences observed in Parkin and P62 regulation. Our study revealed cell type-specific regulation of chemerin-CMKLR1 signaling in I/R injury and distinct mitophagy activation mechanisms in microglia and neurons. These findings suggest that the cell type-specific modulation of chemerin-CMKLR1 is a potential therapeutic target for preserving mitochondrial homeostasis; modulating autophagy and mitophagy; and reducing oxidative stress and apoptosis in both microglia and neurons to mitigate I/R injury.