The mechanism of melatonin in promoting FUNDC1-dependent neuronal mitophagy in sepsis-related encephalopathy

Background: Sepsis-associated encephalopathy (SAE), a critical complication in ICU patients, leads to high mortality and cognitive impairment. Mitochondrial dysfunction and neuroinflammation are central to SAE pathogenesis, yet the regulatory role of FUNDC1 and therapeutic potential of melatonin remain undefined.

Methods: Wild-type, FUNDC1 knockout (KO), and FUNDC1 transgenic (TG) mice were subjected to LPS-induced SAE. Cognitive function was assessed via morris water maze and open field tests. Mitochondrial morphology, autophagy markers (LC3-II, Beclin1, P62), pyroptosis-related proteins (NLRP3, caspase-1, IL-1β), and energy metabolism were analyzed using electron microscopy, qRT-PCR, Western blot, and high-performance liquid chromatography. Primary hippocampal neurons and HT22 cells under LPS stimulation were used for in vitro validation. Results: In SAE mice, FUNDC1 expression was significantly reduced (P < 0.01), accompanied by impaired mitophagy (decreased LC3-II and Beclin1, increased P62; P < 0.01), mitochondrial dysfunction (elevated ROS, reduced ATP; P < 0.01), and enhanced pyroptosis (upregulated NLRP3, caspase-1, and IL-1β; P < 0.001). Melatonin treatment significantly restored FUNDC1 levels, promoted mitophagy, and suppressed pyroptosis (P < 0.001). FUNDC1 KO mice exhibited severe cognitive deficits with prolonged escape latency, reduced platform crossings, which were ameliorated by melatonin. In vitro, FUNDC1 KO neurons showed reduced viability and mitochondrial membrane potential , both rescued by melatonin (all P < 0.01). Conclusion: This study identifies FUNDC1 as a pivotal regulator of mitochondrial quality control and pyroptosis in SAE. Melatonin mitigates neuronal injury by restoring FUNDC1-mediated mitophagy and inhibiting NLRP3 inflammasome activation, offering a novel therapeutic strategy for SAE.