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Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress.

ABSTRACT: AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes to phosphorylate targets such as ACC1 and SREBP1c, exerting early anti-anabolic and pro-catabolic roles. Moderate increases in AMP expand this to activate cytosolic AMPK also in an AXIN-dependent manner. In contrast, high concentrations of AMP, arising from severe nutrient stress, activate all pools of AMPK independently of AXIN. Surprisingly, mitochondrion-localized AMPK is activated to phosphorylate ACC2 and mitochondrial fission factor (MFF) only during severe nutrient stress. Our findings reveal a spatiotemporal basis for hierarchical activation of different pools of AMPK during differing degrees of stress severity.

SUBMITTER: Zong Y

PROVIDER: S-EPMC6796943 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress.

Zong Yue Y Zhang Chen-Song CS Li Mengqi M Wang Wen W Wang Zhichao Z Hawley Simon A SA Ma Teng T Feng Jin-Wei JW Tian Xiao X Qi Qu Q Wu Yu-Qing YQ Zhang Cixiong C Ye Zhiyun Z Lin Shu-Yong SY Piao Hai-Long HL Hardie D Grahame DG Lin Sheng-Cai SC

Cell research 20190404 6

AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes ...[more]

PMID: 30948787

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Project description:Ginkgolide B (GB), the diterpenoid lactone compound isolated from the extracts of Ginkgo biloba leaves, significantly improves cognitive impairment, but its potential pharmacological effect on astrocytes induced by β‑amyloid (Aβ)1‑42 remains to be elucidated. The present study aimed to investigate the protective effect and mechanism of GB on astrocytes with Aβ1‑42‑induced apoptosis in Alzheimer's disease (AD). Astrocytes obtained from Sprague Dawley rats were randomly divided into control, Aβ, GB and GB + compound C groups. Cell viability and apoptosis were analyzed using Cell Counting Kit‑8 and flow cytometry assays, respectively. Protein and mRNA expression levels were analyzed using western blotting and reverse transcription‑quantitative PCR, respectively. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH‑Px), reactive oxygen species (ROS) and ATP were determined using the corresponding commercial kits. The findings revealed that GB attenuated Aβ1‑42‑induced apoptosis and the 5' adenosine monophosphate‑ activated protein kinase (AMPK) inhibitor compound C reversed the protective effects of GB. In addition, GB reversed Aβ1‑42‑induced oxidative damage and energy metabolism disorders, including decreases in the levels of SOD, GSH‑Px and ATP and increased the levels of MDA and ROS in astrocytes, while compound C reversed the anti‑oxidative effect and the involvement of GB in maintaining energy metabolism in astrocytes. Finally, GB decreased the expression levels of the endoplasmic reticulum stress (ERS) proteins and the apoptotic protein CHOP and increased both mRNA and protein expression of the components of the energy metabolism‑related AMPK/peroxisome proliferator‑activated receptor γ coactivator 1α/peroxisome proliferator‑activated receptor α and anti‑oxidation‑related nuclear respiratory factor 2/heme oxygenase 1/NAD(P)H dehydrogenase (quinone 1) pathways and downregulated the expression of β‑secretase 1. However, compound C could antagonize these effects. In conclusion, the findings demonstrated that GB protected against Aβ1‑42‑induced apoptosis by inhibiting ERS, oxidative stress, energy metabolism disorders and Aβ1‑42 production probably by activating AMPK signaling pathways. The findings provided an innovative insight into the treatment using GB as a therapeutic in Aβ1‑42‑related AD.

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Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress.

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Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress.

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