EFHD1 promotes osteosarcoma proliferation and drug resistance by inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP) by binding to ANT3

• Published in: Cellular and molecular life sciences : CMLS 2024-12, Vol.81 (1), p.236-236, Article 236
• Main Authors: Shen, Xin, Ma, Mengjun, Mi, Rujia, Zhuang, Jiahao, Song, Yihui, Yang, Wen, Li, Hongyu, Lu, Yixuan, Yang, Biao, Liu, Yinliang, Wu, Yanfeng, Shen, Huiyong
• Format: Article
• Language: English
• Subjects: Adenine; Adenine Nucleotide Translocator 3 - genetics; Adenine Nucleotide Translocator 3 - metabolism; Animals; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Biology; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - drug effects; EF-hand; Humans; Inhibitors; Life Sciences; Membrane permeability; Membranes; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial permeability transition pore; Mitochondrial Permeability Transition Pore - metabolism; Nucleotides; Original; Original Article; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - pathology; Permeability; Protein Binding; Sarcoma; Translocase
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-024-05254-8

Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.