An Insight into Neuronal Processing of Ghrelin: Effects of a Bioactive Ghrelin Derivative on Proteolytic Pathways and Mitophagy

Protein homeostasis (proteostasis) is preserved by an orchestrated network of molecular mechanisms that regulate protein synthesis, folding, and degradation, ensuring cellular integrity and function. Proteostasis declines with age and is related to pathologies such as neurodegenerative diseases and cardiac disorders, which are accompanied by the accumulation of toxic protein aggregates. In this context, therapeutic strategies enhancing the two primary degradative systems involved in the cellular clearance of those abnormal proteins, namely ubiquitin–proteasome system and autophagy-lysosomal pathway, represent a promising approach to counteract the collapse of proteostasis in such pathological conditions. In this work, we explored the processing of ghrelin, a pleiotropic peptide hormone linked to energy metabolism and higher brain functions, which is reported to modulate the protein degradative mechanisms. According to our data, ghrelin is processed by serine hydrolases secreted into the conditioned medium of SH-SY5Y neuroblastoma cell line, commonly used in neurotoxicology and neuroscience research. Ghrelin processing leads to the formation of a shorter peptide (ghrelin(1–11)) that stimulates both the cell proteasome system and autophagy-lysosomal pathway, encompassing the selective autophagy of mitochondria. Our findings suggest that ghrelin processing may contribute to the maintenance of neuronal proteostasis.