[Abstract] objective: To investigate the effect of bupivacaine (BPV) lipid on cognitive function of elderly anesthesia patients through mitochondrial calcium signal axis modulation. Methods: Sixty-one American Association of Anesthesiologists (ASA) class I or II patients aged 65-85 who underwent total hip replacement in our hospital from January 2022 to December 2024 were selected as the research objects. Anesthesia methods were spinal anesthesia combined with bupivacaine liposome for pericapsular nerve block of hip joint. Patients were divided into POCD group (n=15) and non-POCD group (n=46) according to whether POCD appeared 7 days after operation. The activity levels of respiratory chain complexes Ⅰ, Ⅱ, Ⅲ, Ⅳ in mitochondrial membrane of peripheral blood leukocytes were detected by ELISA kit. Thirty-six 18-month-old C57BL/6 male mice were randomly divided into control group, postoperative cognitive impairment (POCD) group and POCD+ASM981 group, with 12 mice in each group. Except for the control group, other groups of mice were injected with 0.5% bupivacaine through femoral vein. Morris water maze (MWM) was used to evaluate the spatial memory and learning ability of mice, and the activation of AMP-dependent protein kinase (AMPK) and power-related protein 1(Drp1) was analyzed by western blot. Primary neurons were divided into three groups: blank (Con) group, BPV group, ASM981 group and BPV+ASM981 group. Except Con group and ASM981 group, other groups were exposed to 1 mmol·L-1 bupivacaine for 12 h. Mitochondria of neurons were observed by MitoTracker Red labeling. Results: Compared with before anesthesia induction, the activities of leukocyte mitochondrial membrane respiratory chain complexes Ⅰ, Ⅱ, Ⅲ and Ⅳ in non-POCD group and POCD group decreased significantly one day after operation (P < 0.05), and the activities of leukocyte mitochondrial membrane respiratory chain complexes Ⅰ, Ⅱ, Ⅲ and Ⅳ in non-POCD group were higher than those in POCD group (P < 0.05). Compared with Con group, the protein levels of p-AMPK, mito-Drp1 and calcineurin in primary neurons in BPV group increased significantly (P < 0.05), while the protein level of p637-Drp1 and the length of mitochondrial branches decreased significantly (P < 0.05). The levels of p-AMPK, mito-Drp1 protein and calcineurin in primary neurons of BPV+ASM981 group were lower than those of BPV group (P < 0.05), while the levels of p637-Drp1 protein and the length of mitochondrial branches were higher than those of BPV group (P < 0.05). Compared with POCD group, mice in POCD+ASM981 group spent less time to escape the incubation period, crossed the platform more times, stayed on the platform longer, and reduced the distance to the target quadrant (P < 0.05). The level of p637-Drp1 in hippocampus of POCD+ASM981 group was higher than that of POCD group (P < 0.05), and the level of mito-Drp1 in mitochondria was lower (P < 0.05). Conclusion: ASM981 has protective effect on cognitive dysfunction induced by BPV in aged mice, and the mechanism may be to improve mitochondrial dysfunction by inhibiting mitosis mediated by AMPK signaling pathway.