Conformational change of adenine nucleotide translocase‐1 mediates cisplatin resistance induced by EBV‐LMP1

Adenine nucleotide translocase‐1 (ANT1) is an ADP/ATP transporter protein located in the inner mitochondrial membrane. ANT1 is involved not only in the processes of ADP/ATP exchange but also in the composition of the mitochondrial membrane permeability transition pore (mPTP); and the function of ANT1 is closely related to its own conformational changes. Notably, various viral proteins can interact directly with ANT1 to influence mitochondrial membrane potential by regulating the opening of mPTP, thereby affecting tumor cell fate. The Epstein–Barr virus (EBV) encodes the key tumorigenic protein, latent membrane protein 1 (LMP1), which plays a pivotal role in promoting therapeutic resistance in related tumors. In our study, we identified a novel mechanism for EBV‐LMP1‐induced alteration of ANT1 conformation in cisplatin resistance in nasopharyngeal carcinoma. Here, we found that EBV‐LMP1 localizes to the inner mitochondrial membrane and inhibits the opening of mPTP by binding to ANT1, thereby favoring tumor cell survival and drug resistance. The ANT1 conformational inhibitor carboxyatractyloside (CATR) in combination with cisplatin improved the chemosensitivity of EBV‐LMP1‐positive cells. This finding confirms that ANT1 is a novel therapeutic target for overcoming cisplatin resistance in the future. SYNOPSIS EBV‐encoded tumorigenic protein LMP1 regulates conformational changes of mitochondrial protein adenine nucleotide translocase‐1 (ANT1), and thereby chemoresistance of tumor cells. Direct interaction of the EBV‐encoded tumorigenic protein LMP1 with ANT1 in the mitochondria induced its conformational change. EBV‐LMP1 fixed ANT1 conformation in the m‐state, increased mitochondrial membrane potential, inhibited mitochondrial ADP/ATP exchange rate and decreased oxidative phosphorylation levels, which led to increased NPC cell viability. Carboxyatractyloside (CATR) targeted conformational changes of ANT1 and enhanced the sensitivity of tumor cells to cisplatin. Graphical Abstract EBV‐encoded tumorigenic protein LMP1 regulates conformational changes of mitochondrial protein adenine nucleotide translocase‐1 (ANT1), and thereby chemoresistance of tumor cells.