Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2.
Vertebrate female reproduction is limited by the oocyte stockpiles acquired during embryonic development. These are gradually depleted over the organism's lifetime through the process of apoptosis. The timer that triggers this cell death is yet to be identified. We used the Xenopus egg/oocyte system to examine the hypothesis that nutrient stores can regulate oocyte viability. We show that pentose-phosphate-pathway generation of NADPH is critical for oocyte survival and that the target of this regulation is caspase-2, previously shown to be required for oocyte death in mice. Pentose-phosphate-pathway-mediated inhibition of cell death was due to the inhibitory phosphorylation of caspase-2 by calcium/calmodulin-dependent protein kinase II (CaMKII). These data suggest that exhaustion of oocyte nutrients, resulting in an inability to generate NADPH, may contribute to ooctye apoptosis. These data also provide unexpected links between oocyte metabolism, CaMKII, and caspase-2.
Nutt
Leta K
LK
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Margolis
Seth S
SS
Jensen
Mette
M
Herman
Catherine E
CE
Dunphy
William G
WG
Rathmell
Jeffrey C
JC
Kornbluth
Sally
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D009249:NADP / Q000096:biosynthesis; D009865:Oocytes / Q000201:enzymology / Q000378:metabolism*; D009866:Oogenesis / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000502:physiology; D010766:Phosphorylation; D012098:Reproduction / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014982:Xenopus laevis
D009249:NADP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053143:Caspase 2; D020169:Caspases; D005947:Glucose