TMEM165 is a divalent cation:proton antiporter localized to the Golgi and lysosomal membranes that mediates bidirectional transport of calcium and manganese ions 1. The protein functions as a Ca2+/Mn2+:H+ antiporter, pumping metal ions into organellar lumens while extruding protons, driven by the proton gradient and membrane potential 2. This transport activity supplies essential cofactors to resident glycosylation enzymes and maintains proper luminal pH for secretory pathway function 1. At the Golgi, TMEM165 is critical for N- and O-glycosylation and lipid glycosylation by maintaining sufficient manganese availability for glycosyltransferase activity 1. Manganese insufficiency in TMEM165-deficient cells causes glycosylation defects that can be rescued by manganese supplementation, identifying Golgi Mn2+ homeostasis as central to its function 3. Recently, lysosomal TMEM165 was identified as a proton-activated calcium importer essential for lysosomal calcium refilling and cellular ion homeostasis 4, promoting calcium-induced proton leakage and enhancing cell survival during calcium overload 5. Mutations in TMEM165 cause Congenital Disorder of Glycosylation 2K, with disease-causing variants showing reduced transport activity 2. Beyond glycosylation disease, TMEM165 overexpression promotes glioblastoma progression through epithelial-mesenchymal transition and chemoresistance 6, establishing its role in cancer pathophysiology.