Metabolic Activation of CaMKII by Coenzyme A

McCoy, Francis; Darbandi, Rashid; Lee, Hoi Chang; Bharatham, Kavitha; Moldoveanu, Tudor; Grace, Christy R.; Dodd, Keela; Lin, Wenwei; Chen, Si Ing; Tangallapally, Rajendra; Kurokawa, Manabu; Lee, Richard; Shelat, Anang A.; Chen, Taosheng; Green, Douglas R.; Harris, Robert A.; Lin, Sue Hwa; Fissore, Rafael A.; Colbran, Roger J.; Nutt, Leta K.

doi:10.1016/j.molcel.2013.08.043

Cited by 34 publications

(31 citation statements)

References 36 publications

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“…Following Ca 2ϩ /CaM dissociation, Thr(P) 286 CaM-KII remains active, and further autophosphorylation occurs at Thr 305 , Thr 306 , and Ser 314 (21,22). Recently, the Nutt laboratory reported that CoA, generated in Xenopus egg extracts in the presence of abundant nutrients, binds to and activates CaMKII (23). We show here that nutrientdriven CaMKII activation additionally requires release of a "brake."…”

mentioning

confidence: 57%

Metabolic Control of Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)-mediated Caspase-2 Suppression by the B55β/Protein Phosphatase 2A (PP2A)

Huang¹,

Yang²,

Wojton³

et al. 2014

Journal of Biological Chemistry

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Background: CaMKII autophosphorylates at Thr 286 in cell-free lysates supplemented with glucose-6-phosphate (G6P). Results: The B55␤ and C subunits of PP2A interact with and dephosphorylate CaMKII at novel sites following addition of G6P. Conclusion: B55␤/PP2A is critical for stimulating CaMKII in the presence of G6P. Significance: This work identifies a novel role for a specific phosphatase complex in controlling CaMKII.

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mentioning

confidence: 57%

Metabolic Control of Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)-mediated Caspase-2 Suppression by the B55β/Protein Phosphatase 2A (PP2A)

Huang¹,

Yang²,

Wojton³

et al. 2014

Journal of Biological Chemistry

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“…A plausible model is suggested by the fact that FA decrease the free CoA/acyl-CoA ratio, resulting in reduced activation of calcium/calmodulin regulated protein kinase II (CAMKII) and consequent decreases in CAMKII-mediated phosphorylation of caspase-2 at Serine-135. Because such phosphorylation typically inactivates caspase-2, its activity might increase as FA accumulate 30. Caspase-2 may also be activated by tumour necrosis factor (TNF)-α.…”

Section: Discussionmentioning

confidence: 99%

Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis

Machado

Michelotti

Pereira

et al. 2014

Gut

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Objective Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg. DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. Design Caspase-2 was localized in liver biopsies from NASH patients. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild type (WT) and caspase-2 deficient mice. Lipotoxicity was modeled in vitro using hepatocytes derived from WT and caspase-2 deficient mice. Results We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localized in injured hepatocytes and its expression was markedly up-regulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of pro-fibrogenic Hedgehog target genes in mice, and blocked production of Hedgehog ligands in cultured hepatocytes. Conclusion These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo, for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.

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“…During the synthesis of fatty acids, acetyl-CoA is consumed and CoA is produced. CoA acts directly on Ca 2+ /calmodulin-dependent protein kinase II (CamKII) to reduce its requirement for Ca 2+ ions, thus effectively activating it (71). One target of the enzymatic activity of CamKII is caspase-2, which upon phosphorylation is sequestered and kept inactive by 14-3-3ζ (72).…”

Section: Metabolic Checkpoints In Cell Fate: Signals Sensors Transdmentioning

confidence: 99%

Metabolic control of cell death

Green

Galluzzi

Kroemer

2014

Science

557

389

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Summary Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries including oxidative phosphorylation and transport of metabolites across membranes may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of “metabolic checkpoints” that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.

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Metabolic Activation of CaMKII by Coenzyme A

Cited by 34 publications

References 36 publications

Metabolic Control of Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)-mediated Caspase-2 Suppression by the B55β/Protein Phosphatase 2A (PP2A)

Metabolic Control of Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)-mediated Caspase-2 Suppression by the B55β/Protein Phosphatase 2A (PP2A)

Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis

Metabolic control of cell death

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