Selective impairment of molecular interaction between ADP and ATP synthase by anesthetics

Background Isoflurane, sevoflurane, and desflurane have been shown to have different neurotoxic effects. However, the underlying mechanism at the single molecular level remains unknown. Isoflurane, sevoflurane, and desflurane can differently induce mitochondrial dysfunction and ATP synthase is the critical component of mitochondrial function. We, therefore, set out to assess whether different anesthetics can selectively impair the interaction of ADP and ATP synthase at a single molecular level. Method The human H4‐APP cells were treated with 2% isoflurane, 4% sevoflurane, or 12% desflurane for 6 hours. The mitochondrial function was measured by using a Seahorse XFp Extracellular Flux Analyzer. Next, we employed a nanobeam technology‐based single molecular dynamic interaction detection method to determine the interaction of ADP and ATP synthase following the administration of isoflurane, sevoflurane, and desflurane. Each of resonance shifts, detected by a nanosensor, corresponded to single molecular interaction of ADP and ATP synthase. Finally, the single molecular dynamics computer simulation was used to identify the binding sites between ATP synthase and each of the anesthetics. Result The Seahorse XFp Extracellular Flux Analyzer demonstrated that isoflurane, but not sevoflurane or desflurane, induced mitochondrial dysfunction in the H4‐APP cells. The nanobeam technology‐based single molecular dynamic interaction detection method demonstrated that isoflurane significantly impaired the interaction of ADP and ATP synthase as evidenced by the decreased numbers of resonance shift, longer duration between the resonance shifts and decreased disassociation constant. Neither sevoflurane nor desfluraneimpaired such interaction. Mechanistically, the single molecular dynamics computer simulation study, assessing the various energy binding ability and different binding dynamic activity, demonstrated that there were 7, 1 and 2 binding sites in ATP synthase by isoflurane, sevoflurane and desflurane, respectively. Note that all of the identified 7 binding sites in ATP synthase by isoflurane are dominated binding position of amino acid related to the generation of ATP. Conclusion These findings suggest that isoflurane has more binding sites with ATP synthase than sevoflurane or desflurane, which impairs the molecular interaction of ADP and ATP synthase, leading to the selective mitochondrial dysfunction and neurotoxicity observed following the administration of isoflurane but not sevoflurane or desflurane.