NDUFA10-Mediated ATP Reduction in Medial Prefrontal Cortex Exacerbates Burst Suppression in Aged Mice

Abstract

Aims: Aging is associated with increased responsiveness to anesthesia-induced burst suppression, which correlates with postoperative cognitive dysfunction and delirium. This study aims to investigate whether the enhanced burst suppression in aged mice under anesthesia is associated with a reduction in ATP levels within the medial prefrontal cortex (mPFC). Methods: EEG recordings were conducted to analyze the burst suppression, and in vivo fiber-optic recording techniques were employed to monitor fluctuations in ATP levels within the mPFC during sevoflurane anesthesia. To elucidate the underlying mechanisms contributing to the observed variations in ATP levels in aged mice, mRNA sequencing was performed. Furthermore, site-specific viral knockdown strategies were implemented to validate the mechanisms of action of key molecules. Results: We observed that sevoflurane anesthesia resulted in an increased burst suppression ratio, extended EEG suppression time, and reduced ATP levels in aged mice. Administration of ATP mitigated the anesthesia-induced increase in EEG suppression time. RNA sequencing revealed that NDUFA10, an energy metabolism-related gene, was down-regulated in aged mice. Knockdown of NDUFA10 in mPFC increased burst suppression, whereas the administration of ATP attenuated these changes. Conclusions: NDUFA10-driven ATP depletion in the mPFC prolongs sevoflurane-induced burst suppression in aged mice, implicating energy metabolism regulation as a strategy to optimize geriatric anesthesia.