The regulator of calcineurin 1 increases adenine nucleotide translocator 1 and leads to mitochondrial dysfunctions

The over‐expression of regulator of calcineurin 1 isoform 1 ( RCAN 1.1) has been implicated in mitochondrial dysfunctions of Alzheimer's disease; however, the mechanism linking RCAN 1.1 over‐expression and the mitochondrial dysfunctions remains unknown. In this study, we use human neuroblastoma SH ‐ SY 5Y cells stably expressing RCAN 1.1S and rat primary neurons infected with RCAN 1.1S expression lentivirus to study the association of RCAN 1 with mitochondrial functions. Our study here showed that the over‐expression of RCAN 1.1S remarkably up‐regulates the expression of adenine nucleotide translocator ( ANT 1) by stabilizing ANT 1 mRNA . The increased ANT 1 level leads to accelerated ATP – ADP exchange rate, more Ca 2+ ‐induced mitochondrial permeability transition pore opening, increased cytochrome c release, and eventually cell apoptosis. Furthermore, knockdown of ANT 1 expression brings these mitochondria perturbations caused by RCAN 1.1S back to normal. The effect of RCAN 1.1S on ANT 1 was independent of its inhibition on calcineurin. This study elucidated a novel function of RCAN 1 in mitochondria and provides a molecular basis for the RCAN 1.1S over‐expression‐induced mitochondrial dysfunctions and neuronal apoptosis.