Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

Mashimo, Tomoyuki; Pichumani, Kumar; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J.; Singh, Dinesh Kumar; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara Grazia Maria; Kovács, Zoltán; Foong, Chan; Huang, Zhi‐Guang; Barnett, Samuel L.; Mickey, Bruce; DeBerardinis, Ralph J.; Tu, Benjamin P.; Maher, Elizabeth A.; Bachoo, Robert

doi:10.1016/j.cell.2014.11.025

Cited by 593 publications

(583 citation statements)

References 34 publications

(45 reference statements)

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“…49 If a reduced flux in acetyl-CoA production was linked to immediate deacetylation, then the acetate generated as a result of histone deacetylation would cause an immediate increase in free acetate, which in turn would constitute a source for acetyl-CoA, hence maintaining stable acetyl-CoA levels. 50,51 Nonetheless, this hypothetical conjecture requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of fasting on human and mouse blood in vivo

et al. 2017

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Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes »20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B C puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.

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Section: Discussionmentioning

confidence: 99%

Metabolic effects of fasting on human and mouse blood in vivo

et al. 2017

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“…The dependence on acetate to supply both nucleocytosolic and mitochondrial acetyl-CoA pools has been identified in multiple cell types, including cancer cells, T cells, and neurons [8][9][10]13,14 . Our study provides evidence for a glucose-derived overflow pathway for acetate metabolism that occurs in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

“…Acetate metabolism provides a parallel pathway for acetylcoA production separate from conversion of citrate to acetyl-CoA by ATP citrate lyase (ACLY) and thus acetate allows for protein acetylation and lipogenesis independent of citrate conversation to acetyl-CoA. This pathway is essential in nutrient deprived tumor microenvironments and other diverse contexts but the origin of acetate has been unclear [8][9][10][11][12][13][14] . It has been postulated that acetate may be synthesized de novo in cells [15][16][17][18][19] but the pathways and quantitative reaction mechanisms through which this may occur are unknown.…”

Section: Introductionmentioning

confidence: 99%

De novo acetate production is coupled to central carbon metabolism in mammals

Liu

et al. 2018

Preprint

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In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.peer-reviewed)

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“…Not surprisingly, tumors utilize a variety of nutrients as carbon sources and energy besides glucose and glutamine, including lipids and acetate [187][188][189] , and may also utilize macropinocytosis to support amino acid pools 22 . However, the circumstances under which macropinocytosis becomes dominant in vivo remain to be established.…”

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

221

108

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

Cited by 593 publications

References 34 publications

Metabolic effects of fasting on human and mouse blood in vivo

Metabolic effects of fasting on human and mouse blood in vivo

De novo acetate production is coupled to central carbon metabolism in mammals

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

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