Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy

Egan, Daniel F.; Shackelford, David B.; Mihaylova, Maria M.; Gelino, Sara; Kohnz, Rebecca A.; Mair, William; Vasquez, Debbie S.; Joshi, Aashish; Gwinn, Dana M.; Taylor, Rebecca C.; Asara, John M.; Fitzpatrick, James A.J.; Dillin, Andrew; Viollet, Benoı̂t; Kundu, Mondira; Hansen, Malene; Shaw, Reuben J.

doi:10.1126/science.1196371

Cited by 2,200 publications

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“…AMPK activates autophagy (Hindupur, González & Hall, 2015) by directly or indirectly activating ULK1 (Egan et al., 2011; Kim, Kundu, Viollet & Guan, 2011). AMPK not only directly phosphorylates and activates ULK1 to induce autophagy, but also indirectly activates ULK1 by inhibiting mTORC1, which phosphorylates and inhibits ULK1 to disrupt the AMPK–ULK1 interaction (Inoki, Kim & Guan, 2012).…”

Section: Discussionmentioning

confidence: 99%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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SummaryMicroglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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“…25 The level of RNAi-mediated knockdown of Atg7, confirmed by RT-qPCR (Supplementary Figure S2), impaired starvation-induced LC3 degradation in WT MEFs, although not to the same level as in Ulk1-deficient MEFs (Figure 2e), and increased susceptibility to cell death after starvation comparable with that observed in Ulk1-deficient MEFs (Figure 2g). 26,27 Atg7 knockdown did not protect against H 2 O 2 -induced cell death in WT or Ulk1-KO MEFs (Figure 2f). Instead, MEFs with Atg7 knockdown or KO were more sensitive to H 2 O 2 treatment than were WT MEFs (Figures 1f and h).…”

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confidence: 93%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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Reactive oxygen species (ROS) may cause cellular damage and oxidative stress-induced cell death. Autophagy, an evolutionarily conserved intracellular catabolic process, is executed by autophagy (ATG) proteins, including the autophagy initiation kinase Unc-51-like kinase (ULK1)/ATG1. Although autophagy has been implicated to have both cytoprotective and cytotoxic roles in the response to ROS, the role of individual ATG proteins, including ULK1, remains poorly characterized. In this study, we demonstrate that ULK1 sensitizes cells to necrotic cell death induced by hydrogen peroxide (H 2 O 2 ). Moreover, we demonstrate that ULK1 localizes to the nucleus and regulates the activity of the DNA damage repair protein poly (ADP-ribose) polymerase 1 (PARP1) in a kinase-dependent manner. By enhancing PARP1 activity, ULK1 contributes to ATP depletion and death of H 2 O 2 -treated cells. Our study provides the first evidence of an autophagy-independent prodeath role for nuclear ULK1 in response to ROS-induced damage. On the basis of our data, we propose that the subcellular distribution of ULK1 has an important role in deciding whether a cell lives or dies on exposure to adverse environmental or intracellular conditions. Cell Death and Differentiation (2016) 23, 216-230; doi:10.1038/cdd.2015; published online 3 July 2015Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide (H 2 O 2 ), are formed by the incomplete reduction of oxygen during oxidative phosphorylation and other enzymatic processes. ROS are signaling molecules that regulate cell proliferation, differentiation, and survival. 1-3 Accumulation of ROS (i.e., oxidative stress) on exposure to xenobiotic agents or environmental toxins can cause cellular damage and death via apoptotic or nonapoptotic pathways. [4][5][6] Oxidative stress-induced cellular damage and death have been implicated in aging, ischemia-reperfusion injury, inflammation, and the pathogenesis of diseases (e.g., neurodegeneration and cancer). 7 Oxidative stress also contributes to the antitumor effects of many chemotherapeutic drugs, including camptothecin 8,9 and selenite. 10,11 Autophagy, an evolutionarily conserved intracellular catabolic process, involves lysosome-dependent degradation of superfluous and damaged cytosolic organelles and proteins. 12 It is typically upregulated under conditions of perceived stress and in response to cellular damage. The consequence of autophagy activation -whether cytoprotective or cytotoxicappears to depend on the cell type and the nature and extent of stress. Although most studies indicate a cytoprotective role for autophagy, some evidence suggests that it contributes to cell death in response to oxidative stress. [13][14][15][16][17] Studies have also indicated that autophagy may be suppressed in response to oxidative stress, thereby sensitizing certain cells to apoptosis. 18,19 Unc-51-like kinase/autophagy 1 (ULK1/ATG1) is a mammalian serine-threonine kinase that regulates flux through the autophagy pathway by activating the VPS34 PI(3) kinas...

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“…9 Loss of AMPK and its downstream target ULK1, a kinase that inhibits autophagy, causes aberrant accumulation of the p62-adaptor-protein and impairment of mitophagy during starvation. 10 Furthermore, p53, the master regulator of genotoxic stress response, is involved in the maintenance of energy homeostasis. p53 functions both in the nucleus and mitochondria and influences mitochondrial physiology in a transcription-dependent and -independent manner.…”

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confidence: 99%

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

2015

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Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and healthspan. Accordingly, impairment of mitochondria has been associated with numerous pathological conditions and ageing. Maintenance of cellular and organismal homeostasis thus hinges on fine-tuning mitochondrial quality control. Mitochondrial biogenesis and mitochondrial selective autophagy (mitophagy), two opposing cellular pathways, coordinately regulate mitochondrial content to sustain energy metabolism, in response to cellular metabolic state, stress and other intracellular or environmental signals. It is not surprising, therefore, that disequilibrium or imbalance between mitochondrial proliferation and degradation processes underlies the onset and progressive unfolding of several pathological conditions in humans, including neurodegenerative diseases, myopathies and other age-associated disorders.Mitochondrial biogenesis is a complex and multistep cellular process, which involves mtDNA transcription and translation, translation of transcripts derived from nucleus, recruitment of newly synthesized proteins and lipids, import and assembly of mitochondrial and nuclear products in the expanding mitochondrial network. Spatiotemporal control of mitochondrial biogenesis is mediated by numerous transcription factors in response to diverse stimuli, including both intracellular signals and environmental stimuli (nutrient availability, growth factors and hormones, toxins, temperature and oxygen fluctuations, among others). The master regulator of mitochondrial energy metabolism is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the best-studied member of the peroxisome proliferator activated receptor family of transcription co-activators, which orchestrates the activity of several transcription factors involved in mitochondrial biogenesis and function. 1 These include the nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) that are part of a complex transcriptional network that regulates mitochondrial biogenesis and energy metabolism. 1,2 Alongside their essential roles in cell and animal physiology, mitochondria are also the major source of potentially hazardous reactive oxygen species as by-products of respiration. Thus, eukaryotic cells have evolved a wide arsenal of quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage and eventual death. Mitophagy, a selective type of autophagy, is triggered upon accumulation of damaged or superfluous mitochondria. Dysfunctional mitochondria are targeted and engulfed by double-membrane vesicles known as autophagosomes and are transferred for degradation in lysosomes. Cells induce mitophagy to regulate the size and quality of their mitochondrial network...

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Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy

Cited by 2,200 publications

References 34 publications

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

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