Objective To investigate the role of the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) /glucose-regulated protein 75 (GRP75) / voltage-dependent anion channel 1 (VDAC1) axis in regulating mitochondrial calcium (Ca²⁺) transport in apoptosis in an in vitro hypoxia-induced injury model of pulmonary artery smooth muscle cells (PASMCs). Methods Rat PASMCs were cultured in vitro and divided randomly into three groups: normal control ( NC) group, hypoxia group, and 4-phenylbutyric acid ( 4-PBA) group. The Ca²⁺concentrations in the endoplasmic reticulum ( ER ), cytoplasm, and mitochondria of PASMCs were measured using Ca²⁺immunofluorescence probes. Mitochondrial structure and morphological changes were observed by transmission electron microscopy and cell apoptosis was detected by flow cytometry. The messenger RNA (mRNA) and protein expression levels of key factors in the Ca²⁺pathway and mitochondrial fission and fusion were determined by quantitative reverse transcription-polymerase chain reaction ( RT-qPCR) and Western blot, respectively. Results Compared with NC group, Ca²⁺concentrations in the ER and cytoplasm of PASMCs were increased, whereas mitochondrial Ca²⁺concentration was decreased in hypoxia group (P<0. 01). Mitochondria showed reduced volume, swelling, disordered cristae structure, and increased rupture, and PASMCs apoptosis was decreased (P<0. 01). The mRNA and protein levels of the key Ca²⁺transport pathway factors IP3R2, GRP75, and VDAC1, and expression of the mitochondrial fission factor dynamin-related protein 1 (DRP1) were all upregulated (P<0. 01), while expression of the mitochondrial fusion factor mitofusin-2 (MFN2) was downregulated (P<0. 01). Compared with hypoxia group,Ca²⁺concentrations in the ER and cytoplasm of PASMCs were decreased, whereas mitochondrial Ca²⁺concentration was increased in 4-PBA group ( P<0. 01). Mitochondrial structure was restored, and expression levels of IP3R2,GRP75, VDAC1, and DRP1 decreased(P<0. 01), while MFN2 expression increased(P<0. 05, P<0. 01), with an increase in PASMCs apoptosis(P<0. 01). Conclusions The IP3R2 / GRP75 / VDAC1 axis enhances mitochondrial Ca²⁺transport in hypoxia-induced PASMCs, promoting PASMCs apoptosis. These result provide a theoretical basis for the prevention and treatment of hypoxic pulmonary hypertension.