Hypersensitivity of A8344G MERRF mutated cybrid cells to staurosporine-induced cell death is mediated by calcium-dependent activation of calpains.
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.
Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (NAmur Research Institute for Life Sciences), University of Namur (FUNDP), Namur, Belgium.
Guillaume
G
Rommelaere
Sébastien
S
Michel
Jérémy
J
Malaisse
Sophie
S
Charlier
Thierry
T
Arnould
Patricia
P
Renard
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D006822:Hybrid Cells; D017243:MERRF Syndrome / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D019311:Staurosporine / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D002154:Calpain; D020169:Caspases; D019311:Staurosporine; D002118:Calcium