7 research outputs found
The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis
No full textAbstract not availableHakan Muyderman, Neil R. Sims, Masashi Tanaka, Noriyuki Fuku, Ravinarayan Raghupathi, Dominic Thyagaraja
RCAN1 regulates mitochondrial function and increases susceptibility to oxidative stress in mammalian cells
No full textPublished 9 June 2014Mitochondria 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 (RCAN1(ox)) 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 (PC12(RCAN1)). Similar to RCAN1(ox) neurons, PC12(RCAN1) 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.Heshan Peiris, Daphne Dubach, Claire F. Jessup, Petra Unterweger, Ravinarayan Raghupathi, Hakan Muyderman, Mark P. Zanin, Kimberly Mackenzie, Melanie A. Pritchard, and Damien J. Keatin
Increased expression of the glucose-responsive gene, RCAN1, causes hypoinsulinemia, Beta-cell dysfunction, and diabetes
No full textData source: Supplementary data, https://doi.org/10.1210/en.2011-2149RCAN1 is a chromosome 21 gene that controls secretion in endocrine cells, regulates mitochondrial function, and is sensitive to oxidative stress. Regulator of calcineurin 1 (RCAN1) is also an endogenous inhibitor of the protein phosphatase calcineurin, the inhibition of which leads to hypoinsulinemia and diabetes in humans and mice. However, the presence or the role of RCAN1 in insulin-secreting β-cells and its potential role in the pathogenesis of diabetes is unknown. Hence, the aim of this study is to investigate the presence of RCAN1 in β-cells and identify its role in β-cell function. RCAN1 is expressed in mouse islets and in the cytosol of pancreatic β-cells. We find RCAN1 is a glucose-responsive gene with a 1.5-fold increase in expression observed in pancreatic islets in response to chronic hyperglycemia. The overexpression of the human RCAN1.1 isoform in mice under the regulation of its endogenous promoter causes diabetes, age-associated hyperglycemia, reduced glucose tolerance, hypoinsulinemia, loss of β-cells, reduced β-cell insulin secretion, aberrant mitochondrial reactive oxygen species production, and the down-regulation of key β-cell genes. Our data therefore identifies a novel molecular link between the overexpression of RCAN1 and β-cell dysfunction. The glucose-responsive nature of RCAN1 provides a potential mechanism of action associated with the β-cell dysfunction observed in diabetes.Heshan Peiris, Ravinarayan Raghupathi, Claire F. Jessup, Mark P. Zanin, Daisy Mohanasundaram, Kimberly D. Mackenzie, Tim Chataway, Jennifer N. Clarke, John Brealey, P. Toby Coates, Melanie A. Pritchard and Damien J. Keatin
Identification of unique release kinetics of serotonin from guinea-pig and human enterochromaffin cells
No full textThis is the accepted version of the following article: [Raghupathi, R., Duffield, M. D., Zelkas, L., Meedeniya, A., Brookes, S. J. H., Sia, T. C., Wattchow, D. A., Spencer, N. J. and Keating, D. J. (2013), Identification of unique release kinetics of serotonin from guinea-pig and human enterochromaffin cells. The Journal of Physiology, 591: 5959–5975. doi: 10.1113/jphysiol.2013.259796], which has been published in final form at [http://dx.doi.org/10.1113/jphysiol.2013.259796]. In addition, authors may also transmit, print and share copies with colleagues, provided that there is no systematic distribution of the submitted version, e.g. posting on a listserve, network or automated delivery
Carbon-fiber amperometry in the study of exocytosis
No full textPermission to archive book chapters in an institutional repository is not permitted by the publisher, Springer.Our laboratory has utilized a non-invasive method of measuring the release of oxidizable molecules from cells, known as carbon-fiber amperometry.Australian Research Counci
RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells
No full textCopyright © 2014 Heshan Peiris et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.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 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 . Similar to neurons, 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
