RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

Abstract

Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer's disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 (RCAN1ox) and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 (PC12RCAN1). Similar to RCAN1ox neurons, PC12RCAN1 cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS.

RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer’s disease

“…Together with the report that RCAN1 levels increase in the human brain with normal aging [7], these findings suggest a role for chronic RCAN1 overexpression in the age-related progression of AD. RCAN1.1L is the predominant isoform in the brain, and it is overexpression of this isoform in AD and DS brains that has been reported and shown recently to promote AD-like pathophysiology [12, 13, 39, 46, 61]. Interestingly, however, RCAN1.1L overexpression was shown to protect cells initially but facilitated apoptosis after long-term overexpression, whereas both short- and long-term overexpression of the RCAN1.1S isoform facilitated apoptosis [61], suggesting RCAN1.1S may be particularly toxic.…”

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

“…Juvenile islets were isolated at the Institute of Cellular Therapeutics of the Allegheny Health Network (Pittsburgh, Pennsylvania, USA) as previously described (3,4,26). Islets from 12 adult donors (ages 20,21,29,30,40,43,43,48,49,53,60, and 60 years, BMI ranges 24.1-29.6) were obtained from the Integrated Islet Distribution Program (http://iidp.coh.org). Islet function (i.e., glucose-induced insulin secretion) was assessed by islet perifusion assay on the day of arrival, as previously described (57,58).…”

Store-operated Ca2+ entry controls ameloblast cell function and enamel development

“…The former acts both as a protease and a chaperone in the ER reducing the amount of unfolded proteins (23) and the latter degrades misfolded glycoproteins. Regulator of calcineurin-1 (Rcan1), a marker for ER stress (24), was also upregulated ( Figure 5E). We confirmed increased expression of HtrA4 and Rcan1 in Stim1/2-deficient cells by qRT-PCR ( Figure 5F).…”