PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway

Abstract

Post-operative cognitive dysfunction (POCD) is a cognitive disorder characterized by a decline in cognitive function following surgical procedures, with mitophagy identified as a significant underlying mechanism. Protein kinase C delta (PRKCD), localized within the mitochondria, is implicated in the regulation of PINK1/PRKN mitophagy pathway; however, the potential regulatory role of PRKCD in POCD through this pathway remains to be elucidated. Neurons and rats were exposed to sevoflurane (SEV) to illuminate the function and mechanism of PRKCD in POCD. Various methodologies were employed, including immunofluorescence, quantitative real-time PCR, CCK-8 assays, mitochondrial membrane potential (MMP) assessments, MitoSOX generation detection, Seahorse metabolic flux analysis, co-immunoprecipitation, western blotting and behavioural experiments like Morris water maze, novel object recognition and fear conditioning, along with haematoxylin and eosin and immunohistochemical staining. PRKCD was expressed in neurons and that SEV administration led to an upregulation of PRKCD expression. Furthermore, interference with PRKCD was found to restore cell viability in SEV-treated neurons. Additionally, inhibition of PRKCD resulted in the recovery of LC3 expression and the normalization of p62 levels in neurons subjected to SEV treatment. Suppressing PRKCD restored MMP and OCR, reduced MitoSOX in SEV-affected neurons and interacted with PRKN and PINK1, decreasing their expression. Overexpressing PRKN mitigated PRKCD inhibition's impact on mitochondrial damage. In vivo, SEV increased PRKCD, PINK1 and PRKN levels, but PRKCD knockdown improved behavioural and pathological outcomes, reversing changes in LC3-II, PINK1, PRKN and p62 expression. PRKCD enhanced SEV-induced POCD in aged rats via the regulation of PINK1/PRKN mitophagy pathway.