The sodium-proton exchangers (NHE) antiporters of the CPA1 family, catalyze Na+ and H+ exchange. NHE activity is also involved in other cellular events such as cell migration, adhesion and proliferation in response to growth factors. Nhedc2 is a novel member of the CPA family and is the first mitochondrial NHA characterized to date. It is also unique in that it is the first eukaryotic and tissue-specific CPA2 characterized to date. Nhedc2 is localized to the mitochondria, where it mediates Na+-dependent exchanges in mitochondrial PH and Na+ acetate induced mitochondrial passive swelling. It is strongly upregulated during RANKL-induced osteoclast differentiation in vivo and in vitro. RNA silencing of this gene reduces osteoclast differentiation and resorption, suggesting that it plays a key role(s) in normal osteoclast differentiation and function.