Hypersensitivity of A8344G MERRF mutated cybrid cells to staurosporine-induced cell death is mediated by calcium-dependent activation of calpains |
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Authors: | Rommelaere Guillaume Michel Sébastien Malaisse Jérémy Charlier Sophie Arnould Thierry Renard Patricia |
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Institution: | Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (NAmur Research Institute for Life Sciences), University of Namur (FUNDP), 61 rue de Bruxelles, 5000 Namur, Belgium |
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Abstract: | Mutations in the mitochondrial DNA can lead to the development of mitochondrial diseases such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF) or Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS). We first show that human 143B-derived cybrid cells harboring either the A8344G (MERRF) or the A3243G (MELAS) mutation, are more prone to undergo apoptosis then their wild-type counterpart, when challenged with various apoptotic inducers such as staurosporine, etoposide and TRAIL. In addition, investigating the mechanisms underlying A8344G cybrid cells hypersensitivity to staurosporine-induced cell death, we found that staurosporine treatment activates caspases independently of cytochrome c release in both wild-type and mutated cells. Caspases are activated, at least partly, through the activation of calcium-dependent calpain proteases, a pathway that is more strongly activated in mutated cybrid cells than in wild-type cells exposed to staurosporine. These results suggest that calcium homeostasis perturbation induced by mitochondrial dysfunction could predispose cells to apoptosis, a process that could take part into the progressive cell degeneration observed in MERRF syndrome, and more generally in mitochondrial diseases. |
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Keywords: | CPEO Chronic Progressive External Ophthalmoplegia KSS Kearns-Sayre Syndrome LHON Leber's Hereditary Optic Neuropathy MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes MERRF Myoclonic Epilepsy with Ragged Red Fibers MILS Maternally Inherited Leigh Syndrome PARP-1 Poly (ADP-Ribose) Polymerase 1 ROS Reactive Oxygen Species STS staurosporine TRAIL TNF-α Related Apoptosis Inducing Ligand |
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