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bioRxiv · 10.1101/2025.07.28.667159

Chemerin-CMKLR1 mediated OGD/R induced Mitochondrial Dysfunction, Oxidative Stress, and Autophagy differentially in Microglia and Neurons

Long, P.-Y.·Tang, Z.·Cai, N.·Yan, Z.-Q.·Gao, X.·Wang, Z.-W.·Guan, Z.-Z.·Qi, X.-L.·Ni, R.·Xiao, Y.
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Abstract

IntroductionIschemia-reperfusion (I/R) injury exacerbates tissue damage upon reperfusion after ischemia. The impact of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1) on I/R injury remains poorly understood. We hypothesized that chemerin-CMKLR1 differentially regulates signaling in microglia and neuronal cells oxygen-glucose deprivation/reoxygenation (OGD/R), influencing mitochondrial function, oxidative stress, and autophagy. MethodsUsing BV2 microglia and Neuro-2a (N2a) neuronal cells, we examined OGD/R-induced changes in autophagy associated proteins, chemerin and CMKLR1 expression. 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. ResultsOGD/R downregulated CMKLR1 while upregulating autophagy in both BV2 microglia and N2a cells; While chemerin expression decreased in BV2 microglia but increased in N2a cells following OGD/R. 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. CMKLR1 overexpression exacerbated mitochondrial respiratory dysfunction, mitochondrial fusion, fission, and elevated autophagy (LC3II/LC3I and Pink1 levels), with cell-type-specific differences observed in Parkin and P62 regulation. ConclusionOur study demonstrates cell-type-specific regulation of chemerin-CMKLR1 signaling in I/R injury, and distinct mitophagy activation mechanisms in microglia and neurons. These findings suggest cell-type specific modulation of chemerin-CMKLR1 as a potential therapeutic target in preserving mitochondrial homeostasis, modulating autophagy, mitophagy and reducing oxidative stress, apoptosis in both microglia and neurons for mitigating I/R injury.

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Long, P.-Y., Tang, Z., Cai, N., Yan, Z.-Q., Gao, X., Wang, Z.-W., Guan, Z.-Z., Qi, X.-L., Ni, R., Xiao, Y.. 2025-07-31. Chemerin-CMKLR1 mediated OGD/R induced Mitochondrial Dysfunction, Oxidative Stress, and Autophagy differentially in Microglia and Neurons. https://doi.org/10.1101/2025.07.28.667159

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