LETM2 (leucine zipper and EF-hand containing transmembrane protein 2) is a mitochondrial inner membrane protein that regulates mitochondrial calcium ion transport and mitochondrial homeostasis. As a transmembrane transporter, LETM2 maintains mitochondrial function and morphology, with structural homology to LETM1, its paralogue that regulates mitochondrial volume 1. LETM2 is expressed preferentially in testis and sperm 1 and plays critical roles in preserving mitochondrial function under oxidative stress conditions. In diabetic foot ulcers, LETM2 knockdown in endothelial cells impairs mitochondrial fission and mitophagy, decreasing cell viability and increasing apoptosis 2. In gastric cancer, LETM2 overexpression promotes tumor proliferation and metastasis by activating the mTOR pathway, maintaining mitochondrial homeostasis, and promoting glycolysis 3. LETM2 is located at chromosome 8.23, a region frequently amplified in multiple cancers including squamous cell lung carcinomas (11.5-17.7% of cases) and esophageal squamous cell carcinoma 456. While LETM2 amplification is common in these malignancies, it shows no significant adverse effect on overall or relapse-free survival in lung cancer 4. LETM2 emerges as a potential therapeutic target for mitochondrial dysfunction-related diseases.