AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation

Chang, Chunmei; Su, Hua; Zhang, Danhong; Wang, Yusha; Shen, Qiuhong; Liu, Bo; Huang, Rui; Zhou, Tian; Peng, Chao; Wong, Catherine C. L.; Shen, Han; Lippincott‐Schwartz, Jennifer; Liu, Wei

doi:10.1016/j.molcel.2015.10.037

Cited by 231 publications

(189 citation statements)

References 54 publications

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“…Previous studies have shown that during starvation, SIRT1 separates from the inhibitory molecule CCAR2/DBC1, and then gets activated by AMP-activated protein kinase (AMPK). 11,12 In the present study, BRD4 is found to form a complex with SIRT1 and CCAR2. Starvation can disrupt the SIRT1-CCAR2 interaction, whereas inhibition or silencing of AMPK does not.…”

Section: 10supporting

confidence: 53%

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Wen

Klionsky

2017

Autophagy

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Section: 10supporting

confidence: 53%

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Wen

Klionsky

2017

Autophagy

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“…One potential regulatory mechanism following adrenergic stimulation is phosphorylation of GAPDH to increase activity (40,41). Studies have shown several kinases regulated by adrenergic stimulation; including Akt/PKB, CaMKIIβ, PKC, and AMPK, phosphorylate GAPDH to enhance activity (42)(43)(44)(45). Thus, the observed decrease in the ration of phosphorylated to total GAPDH protein in adrenergic-deficient embryos is consistent with the decreased enzymatic activity observed for GAPDH in these embryos.…”

Section: Glyceraldehyde-3-phosphatesupporting

confidence: 65%

Metabolomics reveals critical adrenergic regulatory checkpoints in glycolysis and pentose–phosphate pathways in embryonic heart

Peoples

Maxmillian

et al. 2018

Journal of Biological Chemistry

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Cardiac energy demands during early embryonic periods are sufficiently met through glycolysis, but as development proceeds, oxidative phosphorylation in mitochondria becomes increasingly vital. Adrenergic hormones are known to stimulate metabolism in adult mammals and are essential for embryonic development, but relatively little is known about their effects on metabolism in the embryonic heart. Here, we show that embryos lacking adrenergic stimulation have approximately 10-fold less cardiac ATP compared to littermate controls. Despite this deficit in steady-state ATP, neither the rates of ATP formation or degradation were affected in adrenergic-deficient hearts, suggesting that ATP synthesis and hydrolysis mechanisms were fully operational. We thus hypothesized that adrenergic hormones stimulate metabolism of glucose to provide chemical substrates for oxidation in mitochondria. To test this hypothesis, we employed a metabolomics-based approach using liquid chromatography/mass spectrometry (LC/MS). Our results showed glucose-1-phosphate and glucose-6-phosphate concentrations were not significantly altered, but several downstream metabolites in both glycolytic and pentosephosphate pathways were significantly lower compared to controls. Further, we identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G-6-PDH) as key enzymes in those respective metabolic pathways whose activity was significantly (p < 0.05) and substantially (80% and 40%, respectively) lower in adrenergic-deficient hearts.Addition of pyruvate and to a lesser extent, ribose, led to significant recovery of steady-state ATP concentrations. These results demonstrate that without adrenergic stimulation, glucose metabolism in the embryonic heart is severely impaired in multiple pathways, ultimately leading to insufficient metabolic substrate availability for successful transition to aerobic respiration needed for survival.

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“…Dur ing glu cose de pri va tion, GAPDH is phos pho ry lated by AMPK and is translo cated to the cell nu cleus where it in ter acts with NAD de pen dent deacety lase sir tuin 1 (Sirt1). Both AMPK de pen dent phos pho ry la tion and the nu clear translo ca tion of GAPDH me di ate rapid Sirt1 ac ti va tion, lead ing to the tran scrip tional in duc tion of the au tophagy pro gram [145]. Upon nu tri ent star va tion, can cer cells can sur vive on au tophagy.…”

Section: Metabolic Regulation Of Cancer Cell Deathmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

160

128

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation

Cited by 231 publications

References 54 publications

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Metabolomics reveals critical adrenergic regulatory checkpoints in glycolysis and pentose–phosphate pathways in embryonic heart

Cancer metabolism in space and time: Beyond the Warburg effect

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