Abstract

Mitochondrial dynamics and inter-organelle communication, particularly through mitochondrial-endoplasmic reticulum (Mito-ER) contacts, are critical for neuronal health and function. Perturbations in these contact sites are implicated in various neurodegenerative conditions. Carbamylated Darbepoetin (CdEpo) is a derivative of erythropoietin engineered to retain its neuroprotective properties while eliminating its hematopoietic activity, making it a promising therapeutic agent for central nervous system disorders. This study investigates the effects of CdEpo on the integrity and function of mitochondrial contacts in primary neuronal cultures. Using advanced live-cell imaging and electron microscopy, we quantified the frequency and morphology of Mito-ER and mitochondria-lysosome contacts following CdEpo treatment under both basal and excitotoxic stress conditions. Our findings reveal that CdEpo significantly increases the number and stability of Mito-ER contacts, correlating with enhanced mitochondrial calcium buffering capacity and reduced reactive oxygen species production. Furthermore, CdEpo treatment mitigated the stress-induced disruption of these contacts, suggesting a mechanism for its neuroprotective action. These results highlight a novel cellular target for CdEpo and support its potential as a therapeutic strategy to preserve mitochondrial function and neuronal viability in conditions characterized by mitochondrial contact site dysfunction.