Metabolic Inflexibility: When Mitochondrial Indecision Leads to Metabolic Gridlock

Muoio, Deborah M.

doi:10.1016/j.cell.2014.11.034

Cited by 325 publications

(341 citation statements)

References 55 publications

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“…As a result, the excess carbon from glycolysis is secreted as lactate. Other examples are seen in the cells in diabetic tissues where excess fatty acid oxidation leads to incomplete lipid catabolism and excretion of acyl-carnitines and ketone bodies 2 . Numerous other examples are also apparent such as in the case of excess anabolic substrates released in nucleotide synthesis or the excretion of formic acid during excess one carbon metabolism 3 .…”

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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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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“…Excess supply of energy substrates in obesity and IR is believed to cause mitochondrial dysfunction and increased ROS production [156,201,203,204]. HCHIDs may be causally related to the production of oxidative stress, as the following section shows.…”

Section: Dietary Related Oxidative Stressmentioning

confidence: 99%

“…As insulin controls systemic flux, storage and disposal of glucose, fatty acids and amino acids, insulin sensitivity is a prerequisite for this task [203]. Therefore, development of IR causes significant metabolic perturbations.…”

Section: Citationmentioning

confidence: 99%

“…Basically, mitochondria are able to switch freely between glucose and fatty acid oxidation in order to adjust fuel oxidation to fuel availability (termed as "metabolic flexibility"), but function smoothly only as long as acetyl-CoA is produced from one fuel at a time. Hence, this situation requires nutrient partitioning in order to avoid mitochondrial indecision and metabolic "gridlock" [203].…”

Section: Glucocentric and Adipocentric Metabolismmentioning

confidence: 99%

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Significant Dietary Changes during Human Evolution and the Development of Cancer: From Cells in Trouble to Cells Causing Trouble

Köpp¹

2017

J Carcinog Mutagen

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In all western societies, mortality rates from cancer are high and even increasing. In striking contrast, cancer rates are very rare and even non-existent in primitive cultures, like hunter-gatherer (HG) populations. HGs are free of disease as long as they adhere to their traditional low-insulinemic "Paleolithic" nutrition. With acculturation and transition to current high-carbohydrate/high-insulinemic "Western" diets (HCHIDs), cancer develops in high rates. This paper follows the question of how significant nutritional changes, brought about by the Agricultural revolution, may cause development of cancer. The evidence presented shows that the switch from a Paleolithic to a Western nutrition has brought about significant metabolic perturbations, like an abnormally increased activation of the insulinlike growth factor system, the sympathetic nervous system and the renin-angiotensin-system, an increased expression of HIF-1α and other more, all of which are deeply involved in cancer development through promotion of proliferation, angiogenesis, inflammation, macrophage infiltration, metastasis and inhibition of apoptosis.In addition, HCHIDs generate oxidative stress which may cause mitochondrial damage and genomic instability, and may interfere with normal stem cell development. Faulty redox signaling is suggested to play a significant role in cancer development: hydrogen peroxide, generated at low concentrations, represents an important chemical mediator in the regulation of various cellular signal transduction processes, including stem cell development. Oxidative stress may be sensed by cells as redox signaling. Faulty "redox signaling" is proposed to affect normal stem cell development by sustained activation of uncoupling protein 2, leading to inhibition of differentiation ("maturation arrest"), sustained uncontrolled proliferation, and glycolysis with high expression of hexokinase II, typical features of cancer. In summary, an abnormal diet-related activation of various metabolic systems, together with faulty redox signaling, is suggested to play a pivotal role in cancer development.

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“…Relevance to aging and NAFLD development in human population Muoio (2014) and proposed that the challenge on metabolic flexibility and not leaving the metabolic state at a chronic overnutrition status all the time, are the keys to the health improvement [4,30]. Chronic overnutrition leads to a state of metabolic confusion, wherein excessive carbon supply and heightened substrate competition give rise to a set of intermittent calorie restriction in humans has been reported to increase insulin sensitivity, even more than daily CR that achieves similar weight loss [44,45].…”

Section: Liver Plasticity Induced By the Diet Switchesmentioning

confidence: 99%

Diet-induced phenotypic plasticity during aging

Rusli

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Metabolic Inflexibility: When Mitochondrial Indecision Leads to Metabolic Gridlock

Cited by 325 publications

References 55 publications

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

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

Significant Dietary Changes during Human Evolution and the Development of Cancer: From Cells in Trouble to Cells Causing Trouble

Diet-induced phenotypic plasticity during aging

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