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Monitoring Dynamic Changes In Mitochondrial Calcium Levels During Apoptosis Using A Genetically Encoded Calcium Sensor
Published on: April 1, 2011
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Developmentally regulated ceramide synthase 6 increases mitochondrial Ca2+ loading capacity and promotes apoptosis
Sergei A Novgorodov1, Daria A Chudakova, Brian W Wheeler
1Ralph H Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401, USA.
The Journal of Biological Chemistry
|December 15, 2010
Summary
Ceramide synthase 6 (CerS6) regulates mitochondrial calcium and calpain activity, impacting oligodendrocyte survival during brain development. Down-regulation of CerS6 protects cells from apoptosis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Ceramides are crucial sphingolipids in cell membranes and stress responses.
- Ceramide synthases (CerS1-6) generate various ceramide species.
- Brain development involves dynamic changes in sphingolipid metabolism.
Purpose of the Study:
- To investigate the role of CerS6 in brain development and oligodendrocyte (OL) apoptosis.
- To elucidate the function of CerS6 in mitochondrial calcium homeostasis.
- To determine the link between CerS6, mitochondrial function, and cell survival.
Main Methods:
- Analysis of ceramide species and CerS6 expression during brain development.
- Mitochondrial assays measuring calcium loading capacity.
- Immunoprecipitation to study CerS6 interaction with the mitochondrial permeability transition pore.
- Oligodendrocyte precursor cell culture with genetic manipulation (siRNA) and pharmacological treatments.
Main Results:
- CerS6 expression and C(16:0)-ceramide levels decrease during brain development.
- CerS6 down-regulation impairs mitochondrial calcium uptake.
- CerS6 interacts with the mitochondrial permeability transition pore.
- CerS6 knockdown protects OLs from glutamate- and nerve growth factor-induced apoptosis by modulating mitochondrial calcium and calpain activity.
Conclusions:
- CerS6 plays a critical role in regulating mitochondrial calcium homeostasis and calpain activation.
- CerS6-generated ceramide may prevent mitochondrial permeability transition pore opening.
- Modulating CerS6 activity offers a potential therapeutic strategy for conditions involving OL apoptosis during brain development.
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