AMPK: restoring metabolic homeostasis over space and time

Trefts, Elijah; Shaw, Reuben J.

doi:10.1016/j.molcel.2021.08.015

Cited by 224 publications

(158 citation statements)

References 147 publications

(185 reference statements)

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“…Our effort to identify regulators downstream of MEK-ERK prompted us to consider AMPK, given its previously reported roles in phosphorylating and inactivating ACC 25 , promoting a catabolic switch 26 , and suppressing JNK activity 27,28 . We observed increased AMPK phosphorylation in 83R and M76R cells compared to their parental cells ( Figure 5C ).…”

Section: Resultsmentioning

confidence: 99%

“…By employing shotgun lipidomics, we were able to show that AMPK activation allows GSCs to overcome lipotoxicity, sustain proliferation, and retain their in vivo tumor initiation capacity when DNLS is impaired by altering membrane lipid composition and sequestering toxic SFA into neutral lipids. In light of the role of AMPK in promoting a switch from anabolic to catabolic processes 26 , including the inactivation of ACC 25 , a defined mechanism for this seemingly contradictory upregulation of MUFA and LDs in GSCs with a constitutively active AMPK remains to be elucidated. AMPK increases FA uptake by enhancing the translocation of the FA transporter CD36 to the plasma membrane 46 .…”

Section: Discussionmentioning

confidence: 99%

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Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma

Badr

Eyme

Sammarco

et al. 2022

Preprint

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Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in Glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or particularly in combination with Temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and its ability to impair DNA damage repair. We report that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drives therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs impervious to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Altogether, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for rational integration of DNLS-targeted therapies for the treatment of GBM.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma

Badr

Eyme

Sammarco

et al. 2022

Preprint

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show abstract

“…Other metabolism-regulating kinases also display organelle-specific localization. AMPK exists in distinct cellular pools that localize to different organelles due to the unique regulatory subunit they contain [ 136 ]. A lysosome-localized AMPK pool interacts with multiple protein complexes involved in mTORC1 signaling, such as the FLCN-FNIP complex and the Ragulator-V-ATPase [ [137] , [138] , [139] ].…”

Section: Overview Of Organelle Communication Pathwaysmentioning

confidence: 99%

Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

Jain

Zoncu

2022

Molecular Metabolism

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“…However, the role of FIS1 in mitochondrial life has been a controversial issue since its depletion has a marginal effect on mitochondrial division [ 169 ]. In addition, other perspectives mainly focus on AMPK, which could directly control mitochondrial homeostasis [ 171 ]. Especially, one group demonstrates that inositol can inhibit mitochondrial fission under energy stress by directly targeting AMPKγ subunits [ 172 ].…”

Section: Alteration In Mitochondrial Dynamics and The Fusion/fission Cycle In Neurodegenerative Diseasesmentioning

confidence: 99%

A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases

Hyun

Lee

2021

Antioxidants

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Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.

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AMPK: restoring metabolic homeostasis over space and time

Cited by 224 publications

References 147 publications

Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma

Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma

Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases

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