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

Abstract

The over-expression of regulator of calcineurin 1 isoform 1 (RCAN1.1) has been implicated in mitochondrial dysfunctions of Alzheimer's disease; however, the mechanism linking RCAN1.1 over-expression and the mitochondrial dysfunctions remains unknown. In this study, we use human neuroblastoma SH-SY5Y cells stably expressing RCAN1.1S and rat primary neurons infected with RCAN1.1S expression lentivirus to study the association of RCAN1 with mitochondrial functions. Our study here showed that the over-expression of RCAN1.1S remarkably up-regulates the expression of adenine nucleotide translocator (ANT1) by stabilizing ANT1 mRNA. The increased ANT1 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 ANT1 expression brings these mitochondria perturbations caused by RCAN1.1S back to normal. The effect of RCAN1.1S on ANT1 was independent of its inhibition on calcineurin. This study elucidated a novel function of RCAN1 in mitochondria and provides a molecular basis for the RCAN1.1S over-expression-induced mitochondrial dysfunctions and neuronal apoptosis.

Down Syndrome Critical Region 1 Gene, Rcan1 , Helps Maintain a More Fused Mitochondrial Network

“…Alternative explanations for the decline in coupling efficiency are activation of protective compensatory mechanisms or a direct impact of RCAN1 on mitochondrial coupling. Along these lines it is relevant to note that RCAN has been reported to interact both directly 45 and indirectly 46 with the adenine nucleotide translocase, a protein which can act to uncouple the inner mitochondrial membrane proton gradient. 47…”

Upregulation of RCAN1.4 by HIF1α alleviates OGD‐induced inflammatory response in astrocytes

“…According to our previous studies, RCAN1.1 has been proved to be upregulated in the brain of Down syndrome and Alzheimer's disease, inducing neuronal apoptosis 16 . Recently, we reported that RCAN1.1 is a novel RNA‐binding protein, increasing the adenine nucleotide translocator 1 mRNA, to regulate mitochondrial dysfunctions and neuronal apoptosis 26,38 . However, the distribution and function of RCAN1.4 in the brain have not been characterized in detail, and the effect of RCAN1.4 on ischemic stroke pathogenesis has not been clearly clarified.…”

“…16 Recently, we reported that RCAN1.1 is a novel RNAbinding protein, increasing the adenine nucleotide translocator 1 mRNA, to regulate mitochondrial dysfunctions and neuronal apoptosis. 26,38 However, the distribution and function of RCAN1.4 in the brain have not been characterized in detail, and the effect of RCAN1.4 on ischemic stroke pathogenesis has not been clearly clarified. In the present study, we demonstrated that was significantly upregulated in the infarct region of the MCAO model of ischemic stroke.…”

ANT1 overexpression models: Some similarities with facioscapulohumeral muscular dystrophy

“…Moreover, in lung ischemia-reperfusion (I/R) injury, the protective administration of cyclosporine-A would depend on the decreased expression levels of ANT1 and VDAC1 [ 118 ]. Furthermore, ANT1 overexpression was deleterious in various cell types [ 86 , 87 , 119 ]. ANT1 up-regulation via the overexpression of regulator of calcineurin 1 isoform 1 was detrimental in human neuroblastoma SH‐SY5Y cells, leading to abnormal mitochondria [ 119 ].…”