AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1α-mediated mitochondrial biogenesis

Chaube, Balkrishna; Malvi, Parmanand; Singh, Shivendra V.; Mohammad, Naoshad; Viollet, Benoı̂t; Bhat, Manoj Kumar

doi:10.1038/cddiscovery.2015.63

Cited by 131 publications

(107 citation statements)

References 49 publications

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“…AMPK can promote glycolysis as a survival mechanism upon oxidative stress [53]. AMPK can also promote oxidative metabolism via increasing mitochondrial biogenesis and OXPHOS capacity [54], correlating with a dual metabolic response upon leucine treatment in different systems. Furthermore, β-hydroxy-β-methyl butyrate, a minor metabolite of leucine, has been reported to stimulate AMPK activation insulin sensitivity and fat oxidation [55].…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Kaya

Smith

et al. 2020

JCM

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Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann-Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb -/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

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Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Kaya

Smith

et al. 2020

JCM

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“…This is suggestive of the underlying compensatory function of the Warburg effect. In contrast, ROS induced by low glucose can increase respiration and ATP generation . How opposing types of metabolism are both activated by intracellular oxidation is not well understood, but likely involves an integration of multiple sensory pathways.…”

Section: Cancer Metabolism Is Contextual: a Ros‐dependent Modelmentioning

confidence: 99%

“…In contrast, ROS induced by low glucose can increase respiration and ATP generation. 101 How opposing types of metabolism are both activated by intracellular oxidation is not well understood, but likely involves an integration of multiple sensory pathways. HIF-1 and PGC-1 can both be activated by ROS yet they promote opposite metabolic phenotypes and reciprocally inhibit each other.…”

Section: Cancer Metabolism Is Contextual: a Ros-dependent Modelmentioning

confidence: 99%

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

Rodic

Vincent

2017

Intl Journal of Cancer

152

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Cancer cells exhibit a wide range of metabolic phenotypes, ranging from strict aerobic glycolysis to increased mitochondrial respiration. The cause and utility of this metabolic variation is poorly understood. Given that cancer cells experience heavy selection within their microenvironment, survival requires metabolic adaptation to both extracellular and intracellular conditions. Herein, we suggest that reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype. Intracellular ROS levels can be modified by an assortment of critical parameters including oxygenation, glucose availability and growth factors. ROS act as integrators of environmental information as well as downstream effectors of signaling pathways. Maintaining ROS within a narrow range allows malignant cells to enhance growth and invasion while limiting their apoptotic susceptibility. Cancer cells actively modify their metabolism to optimize intracellular ROS levels and thereby improve survival. Furthermore, we highlight distinct metabolic phenotypes in response to oxidative stress and their tumorigenic drivers.

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“…This mechanism suggests that metabolic pathways might act on the activation of this E3 ligase. Indeed SiaH2 is phosphorylated by p38 MAPK, a downstream target of the AMPK energy sensor (Khurana et al, 2006;Chaube et al, 2015). Interestingly, AMPK can promote mitochondrial biogenesis and oxidative metabolism through the AMPK-p38-PGC-1a axis (Khurana et al, 2006;Chaube et al, 2015).…”

Section: The Role Of Ncor1 In Mitochondrial Functionmentioning

confidence: 99%

Role of NCoR1 in mitochondrial function and energy metabolism

Lima

Valentim

Araújo

et al. 2018

Cell Biology International

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Mitochondrial number and shape are constantly changing in response to increased energy demands. The ability to synchronize mitochondrial pathways to respond to energy fluctuations within the cell is a central aspect of mammalian homeostasis. This dynamic process depends on the coordinated activation of transcriptional complexes to promote the expression of genes encoding for mitochondrial proteins. Recent evidence has shown that the nuclear corepressor NCoR1 is an essential metabolic switch which acts on oxidative metabolism signaling. Here, we provide an overview of the emerging role of NCoR1 in the transcriptional control of energy metabolism. The identification and characterization of NCoR1 as a central, evolutionary conserved player in mitochondrial function have revealed a novel layer of metabolic control. Defining the precise mechanisms by which NCoR1 acts on energy homeostasis will ultimately contribute towards the development of novel therapies for the treatment of metabolic diseases such as obesity and type 2 diabetes.

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AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1α-mediated mitochondrial biogenesis

Cited by 131 publications

References 49 publications

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

Role of NCoR1 in mitochondrial function and energy metabolism

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