The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Marcelo, Kathrina; Means, Anthony R.; York, Brian

doi:10.1016/j.tem.2016.06.001

Cited by 171 publications

(138 citation statements)

References 81 publications

(172 reference statements)

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“…We subsequently explored how mGPDH regulates cytoplasmic CaMKKβ. Previous studies have demonstrated that intracellular Ca 2+ plays an important role in the crosstalk between mitochondria and the cytoplasm (Ganitkevich, ; Fieni et al , ; Stefani et al , ), and Ca 2+ has also been reported to serve as the initiating factor during the cascade involving CaMKKβ‐activated AMPK (Iwabu et al , ; Marcelo et al , ). Therefore, we used a cell membrane‐permeable Ca 2+ chelator, BAPTA‐AM, to eliminate intracellular free Ca 2+ and found that mGPDH‐induced AMPK activation was abolished (Fig R).…”

Section: Resultsmentioning

confidence: 99%

“…Our study also suggests that the effect of mGPDH is mainly through CaMKKβ‐triggered AMPK activation, while LKB1 does not seem to participate in this process. As a calmodulin‐dependent kinase, CaMKKβ activation depends on the intracellular Ca 2+ concentration (Marcelo et al , ). Previous studies have reported that mGPDH regulates the intracellular Ca 2+ concentration in pancreatic beta cells (Eto et al , ,b), which further confirmed our observation regarding the regulation of mGPDH on CaMKKβ.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

Liu

Zheng

et al. 2018

EMBO Mol Med

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While adult mammalian skeletal muscle is stable due to its post‐mitotic nature, muscle regeneration is still essential throughout life for maintaining functional fitness. During certain diseases, such as the modern pandemics of obesity and diabetes, the regeneration process becomes impaired, which leads to the loss of muscle function and contributes to the global burden of these diseases. However, the underlying mechanisms of the impairment are not well defined. Here, we identify mGPDH as a critical regulator of skeletal muscle regeneration. Specifically, it regulates myogenic markers and myoblast differentiation by controlling mitochondrial biogenesis via CaMKKβ/AMPK. mGPDH−/− attenuated skeletal muscle regeneration in vitro and in vivo, while mGPDH overexpression ameliorated dystrophic pathology in mdx mice. Moreover, in patients and animal models of obesity and diabetes, mGPDH expression in skeletal muscle was reduced, further suggesting a direct correlation between its abundance and muscular regeneration capability. Rescuing mGPDH expression in obese and diabetic mice led to a significant improvement in their muscle regeneration. Our study provides a potential therapeutic target for skeletal muscle regeneration impairment during obesity and diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

Liu

Zheng

et al. 2018

EMBO Mol Med

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“…However, it should be noted that AMPK can also be directly phosphorylated on Thr172 in response to calcium flux by the calcium-sensitive kinase CAMKK2 (also known as CAMKKβ) 66–68 , thus linking calcium signalling to the regulation of energy metabolism by AMPK 69 . Increased intracellular calcium activates CAMKK2 and leads to the activation of AMPK independently of LKB1 and nucleotide levels (FIG.…”

Section: Ampk Structure and Activationmentioning

confidence: 99%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,405

1,905

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Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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“…It is established that calcium (Ca 2þ ) binds to intercellular receptor, calmodulin (CaM), and regulate various cellular processes and pathways. [29][30][31] 35,36 AMPK is an enzyme that plays a role in the regulation of energy homeostasis, cytoskeletal organization and cell cycle. 22 CaMKK2 has been shown to phosphorylate and activate protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1; AMPK-a) and these proteins exist as a complex with Ca 2þ /CaM and AMPK-b.…”

Section: Discussionmentioning

confidence: 99%

Investigation of curcumin-mediated signalling pathways in head and neck squamous cell carcinoma

Nanjappa

Sathe

Jain

et al. 2017

Translational Research in Oral Oncology

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Objectives: Curcumin has been shown to exhibit anti-neoplastic effects. However, due to its poor bioavailability, the use of curcumin as an anti-cancer drug is limited. Thus, it is necessary to identify molecules as an alternative to curcumin that could serve as anti-cancer targets. In this study, we attempted to understand the underlying curcumin-mediated signalling pathways contributing to anti-neoplastic effects of curcumin. Methods: We carried out mass spectrometry-based phosphoproteomic analysis of head and neck cancer cell line, CAL 27, treated with and without curcumin to identify curcumin-mediated signalling pathways. Serine/threonine kinases were enriched using titanium dioxide.Results: This resulted in the identification of 5921 phosphopeptides corresponding to 1878 proteins. Of these, 275 and 183 phosphopeptides corresponding to 335 and 242 proteins (!2.0-fold) were found to be hyper-and hypo-phosphorylated, respectively, in response to curcumin treatment. Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/ threonine kinase, and its downstream target protein kinase AMP-activated non-catalytic subunit beta 1 (PRKAB1) were found to be hypo-phosphorylated when treated with curcumin. Further, silencing or inhibiting CaMKK2 resulted in decreased invasion and colony forming ability of not only CAL 27 cells but also other head and neck squamous cell carcinoma (HNSCC) cell lines. Further, Western blot analysis showed that curcumin-mediated signalling is corroborated by CaMKK2. Conclusions: Taken together, our results suggest that CaMKK2 could be a novel therapeutic target in HNSCC and can serve as an alternative to curcumin.

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The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Cited by 171 publications

References 81 publications

Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

AMPK: guardian of metabolism and mitochondrial homeostasis

Investigation of curcumin-mediated signalling pathways in head and neck squamous cell carcinoma

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