Mitochondrial fatty acid oxidase CPT1A ameliorates postoperative cognitive dysfunction by regulating astrocyte ferroptosis

Background: Postoperative cognitive dysfunction (POCD) is a significant surgery-related complication marked by cognitive decline. Studies indicated that neuroinflammation, ferroptosis, and mitochondrial fatty acid metabolism might play parts in POCD, and might be mediated by Carnitine palmitoyl transferase 1a (CPT1A), but requires further investigations. Therefore, this study aims to investigate the mechanism of mitochondrial fatty acid oxidase CPT1A on mitochondrial function, ferroptosis, and inflammation in POCD pathogenesis.

Methods: SVG P12 astrocytes were used to investigate CPT1A's control over mitochondrial function, ferroptosis, and inflammation affecting neurons. CPT1A was overexpressed using shRNA, with or without oligomycin to modulate mitochondrial function. Co-culture of these astrocytes with neurons, under similar conditions, assessed CPT1A's impact on neuron damage via ferroptosis and inflammation. Gene and protein expressions of CPT1A, SYN, PSD95 were measured via RT-PCR and WB. Detection of JC-1, mitochondrial oxygen consumption rate (OCR), ROS, Fe²⁺ concentration, MOD, SOD and GSH/GSSG using kits was conducted to explore mitochondrial function and ferroptosis. Inflammation was quantified by ELISA for IL-6, IL-1β, and TGF-β.

Results: We successfully established CPT1A overexpression and knockdown models in astrocytes, confirming CPT1A's ability to enhance mitochondrial membrane potential. Elevated CPT1A levels led to improved mitochondrial function, synaptic integrity, reduced oxidative stress, maintained iron homeostasis, and attenuated neuroinflammation, as reflected by increased SYN, PSD95, OCR, GSH and SOD, decreased ROS,GSSG, MDA, iron levels, and lowered inflammatory factors expression. Treatment with oligomycin reversed these protective effects, demonstrating the dependency of CPT1A's benefits on intact mitochondrial respiration. In co-culture experiments with hippocampal neurons, astrocytes with manipulated CPT1A levels, particularly those co-treated with oligomycin, exacerbated neuronal mitochondrial dysfunction, oxidative stress, iron accumulation, and inflammation.

Conclusion: Overexpression of mitochondrial fatty acid oxidase CPT1A might improve synaptic integrity and rescue POCD by ameliorating astrocyte ferroptosis and neuroinflammation.