Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy

Tian, Weili; Wen, Li; Chen, Yinqin; Yan, Zeming; Huang, Xiaotong; Zhuang, Haixia; Zhong, Wangtao; Chen, Yusen; Wu, Wenxian; Lin, Chunqing; Chen, Hao; Hou, Xiaoyan; Zhang, Liangqing; Sui, Sen‐Fang; Zhao, Bin; Hu, Zhe; Li, Longxuan; Feng, Du

doi:10.1016/j.febslet.2015.05.020

Cited by 161 publications

(135 citation statements)

References 35 publications

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“…AMPK can also phosphorylate ULK1 at Ser-317 and Ser-777 (73). A S555A mutation in ULK1 prevents recruitment of ULK1 to mitochondria during hypoxic conditions, whereas the S555D mutant that mimics constitutive phosphorylation can traffic to the mitochondria even in the absence of AMPK (74). Most importantly, equivalent mutations in human ULK1 (at Ser-556) had a disparate effect on STING-dependent signaling: S556A ULK1 inhibited STING-dependent signaling, whereas S556D ULK1 had no inhibitory effect (39).…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-␤ induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-␤ and TNF-␣ induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-␤ and TNF-␣ after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-␤ in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells.Pathogen sensing by innate immune cells is essential for host defense in response to invading microorganisms. Recognition by pattern recognition receptors typically activates signal transduction pathways, leading to up-regulation of cytokines like TNF-␣ and IFN-␤. Although IFN-␤ has a well established role in defense against viral infection, intracellular bacterial infections also induce this cytokine. In the past decade, our understanding of the molecular basis for these signaling pathways has expanded greatly and it has been discovered that there is some overlap between proteins responsible for recognition of bacteria and virus alike. One particular example is the mitochondrial and endoplasmic reticulum resident protein stimulator of interferon genes (STING) 2 (1-3). STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7-12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13-15). This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is piv...

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Section: Discussionmentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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“…Coincidently, among its large library of metabolic substrates, AMPK phosphorylates Unc-51-like kinase 1 (ULK)1, a regulator of autophagy [15,16],which can itself regulate AMPK activity by phosphorylation [17]. Inhibiting AMPK-mediated ULK1 phosphorylation leads to accumulation of damaged mitochondria and prevention of mitophagy [15,18]. In addition, AMPK regulates peroxisome proliferator-activated receptor (PPAR)γ co-activator (PGC)-1α, a master transcriptional activator of mitochondrial biogenesis, although whether this regulation is direct (by phosphorylation) or indirect (via SIRT1 deacetylation) is currently still debated [19,20].…”

Section: Figure 1 Mitochondrial Dynamicsmentioning

confidence: 99%

AMPK: keeping the (power)house in order?

Thornton

2017

Neuronal Signaling

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Metabolically energetic organs, such as the brain, require a reliable source of ATP, the majority of which is provided by oxidative phosphorylation in the mitochondrial matrix. Maintaining mitochondrial integrity is therefore of paramount importance in highly specialized cells such as neurons. Beyond acting as cellular 'power stations' and initiators of apoptosis, neuronal mitochondria are highly mobile, transported to pre-and post-synaptic sites for rapid, localized ATP production, serve to buffer physiological and pathological calcium and contribute to dendritic arborization. Given such roles, it is perhaps unsurprising that recent studies implicate AMP-activated protein kinase (AMPK), a cellular energy-sensitive metabolic regulator, in triggering mitochondrial fission, potentially balancing mitochondrial dynamics, biogenesis and mitophagy.Although the brain constitutes approximately only 2% of our total body weight, it accounts for the usage of in excess of 20% of our oxygen intake and is one of the most metabolically active tissues in our bodies. Approximately 90% ATP production occurs through oxidative phosphorylation in mitochondria, therefore, for tissues with a high metabolic rate such as the brain, regulating mitochondrial health is key to sustaining cellular function [1].Mitochondria are dynamic, double-membraned organelles that continually undergo fission, fusion and quality control (mitophagy) [2]. Long-term failure of either fission or fusion can lead to deleterious consequences and thus, a balance of these processes together with mitophagy is critical to maintaining cellular homoeostasis. Over the last 20 years, there has been a flurry of interest in discerning the molecular mechanisms regulating this mitochondrial life cycle, with significant success. Inner and outer mitochondrial membrane fusion are governed by optic atrophy (OPA)1 and mitofusin1/2 respectively whereas fission is mediated by the cytosolic protein, dynamin-related protein (Drp)1 (Figure 1) [3]. Drp1 is recruited to the mitochondrial outer membrane by binding to one of a number of mitochondrially located adaptors such as mitochondrial fission factor (Mff) and mitochondrial fission protein (Fis)1, mitochondrial dynamics proteins of 49 and 51 kDa (MiD49/51) [2,4]. Mitophagy plays a key role in the life cycle of the mitochondrion. Not only does it ensure that damaged mitochondria are neutralized, but physiological mitophagy can also regulate the number of mitochondria and their turnover [5]. In response to the decorating of the outer membrane of a depolarized mitochondrion with ubiquitin, an isolation membrane is recruited to extend round and engulf the mitochondrion, subsequently fusing with a lysosome to acidify and recycle the contents (Figure 1). Fission is frequently observed as a prelude to mitophagy as well as in the initiation of apoptosis [6]. Fusion generates a mitochondrial reticulum, allowing mitochondrial contents to mix, preventing the accumulation of mitochondrial DNA mutations as well as promoting enhanced ATP synthesi...

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“…One study shows that inhibition or knockdown of AMPK prevents ULK1 mitochondrial translocation and inhibits hypoxia-induced mitophagy in MEF cells, suggesting a requirement of AMPK for hypoxia-induced mitophagy[119]. In contrast, another study demonstrates that the percentage of CCCP-induced colocalization of mitochondria and RFP-LC3 puncta is similar in WT and AMPKα1/α2 double knockout MEFs, indicating that AMPK is not essential for CCCP-induced mitophagy[120].…”

Section: Autophagy Mitophagy and Their Regulatory Pathwaysmentioning

confidence: 99%

Mitochondrial quality control in the diabetic heart

Liang

Kobayashi

2016

Journal of Molecular and Cellular Cardiology

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Diabetes is a well known risk factor for heart failure. Diabetic heart damage is closely related to mitochondrial dysfunction and increased ROS generation. However, clinical trials have shown no effects of antioxidant therapies on heart failure in diabetic patients, suggesting that simply antagonizing existing ROS by antioxidants is not sufficient to reduce diabetic cardiac injury. A potentially more effective treatment strategy may be to enhance the overall capacity of mitochondrial quality control to maintain a pool of healthy mitochondria that are needed for supporting cardiac contractile function in diabetic patients. Mitochondrial quality is controlled by a number of coordinated mechanisms including mitochondrial fission and fusion, mitophagy and biogenesis. The mitochondrial damage consistently observed in the diabetic hearts indicates a failure of the mitochondrial quality control mechanisms. Recent studies have demonstrated a crucial role for each of these mechanisms in cardiac homeostasis and have begun to interrogate the relative contribution of insufficient mitochondrial quality control to diabetic cardiac injury. In this review, we will present currently available literature that links diabetic heart disease to the dysregulation of major mitochondrial quality control mechanisms. We will discuss the functional roles of these mechanisms in the pathogenesis of diabetic heart disease and their potentials for targeted therapeutical manipulation.

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Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy

Cited by 161 publications

References 35 publications

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

AMPK: keeping the (power)house in order?

Mitochondrial quality control in the diabetic heart

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