Objective:To evaluate the potential mitochondrial toxicity of A compound,one of DPP-Ⅳ inhibitor hypoglycemic drugs, and to explore the mechanisms of toxicity of A compound. Methods: HepG2 cells were cultured in troglitazone(TRO)50~300 μmol/L for 24 h or A compound 100~300 μmol/L for 24 h. The cell viability was assessed by CCK8 assay. HepG2 cells were cultured in TRO 100,200 and 225 μmol/L for 24 h or A compound 100,150 and 200 μmol/L for 24 h. The level of cellular ATP was detected by luciferase assay. The levels of intracellular free Ca2+,reactive oxygen species(ROS),mitochondrial membrane potential(-驻Ψm)and mitochondrial permeablity transition pore(MPTP)were determined using flow cytometer. Results: Compared with the vehicle control group,TRO at 50~300 μmol/L markedly inhibited cell viability(IC50=178 μmol/L),A compound at 100~300 μmol/L markedly inhibited cell viability(IC50=159 μmol/L). Compared with the vehicle control,levels of ATP and -驻Ψm were significantly decreased in the TRO treated group(≥200 μmol/L)(P < 0.01),levels of ROS were significantly decreased and intracellular free Ca2+ were significantly increased in the TRO treated group (≥100 μmol/L)(P < 0.05 or P < 0.01). After A compound treatment,compared with the vehicle control,levels of ATP and intracellular free Ca2+ were significantly decreased at 100 μmol/L(P < 0.01). A compound at 150 μmol/L increased ROS level significantly (P < 0.01),A compound at 200 μmol/L decreased -驻Ψm level significantly(P<0.05)and mitochondrial ultra-structural changes were observed. Conclusion: DPP-Ⅳ inhibitor A compound can induce mitochondrial toxicity by interfering with mitochondrial metabolism.