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Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.

ABSTRACT: Energy production is inevitably linked to the generation of toxic metabolites, such as reactive oxygen and carbonyl species, known as major contributors to ageing and degenerative diseases. It remains unclear how cells can adapt to elevated energy flux accompanied by accumulating harmful by-products without taking any damage. Therefore, effects of a sudden rise in glucose concentrations were studied in yeast cells. This revealed a feedback mechanism initiated by the reactive dicarbonyl methylglyoxal, which is formed non-enzymatically during glycolysis. Low levels of methylglyoxal activate a multi-layered defence response against toxic metabolites composed of prevention, detoxification and damage remission. The latter is mediated by the protein quality control system and requires inducible Hsp70 and Btn2, the aggregase that sequesters misfolded proteins. This glycohormetic mechanism enables cells to pre-adapt to rising energy flux and directly links metabolic to proteotoxic stress. Further data suggest the existence of a similar response in endothelial cells.

SUBMITTER: Zemva J

PROVIDER: S-EPMC5565788 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.

Zemva Johanna J Fink Christoph Andreas CA Fleming Thomas Henry TH Schmidt Leonard L Loft Anne A Herzig Stephan S Knieß Robert André RA Mayer Matthias M Bukau Bernd B Nawroth Peter Paul PP Tyedmers Jens J

Redox biology 20170812

Energy production is inevitably linked to the generation of toxic metabolites, such as reactive oxygen and carbonyl species, known as major contributors to ageing and degenerative diseases. It remains unclear how cells can adapt to elevated energy flux accompanied by accumulating harmful by-products without taking any damage. Therefore, effects of a sudden rise in glucose concentrations were studied in yeast cells. This revealed a feedback mechanism initiated by the reactive dicarbonyl methylgly ...[more]

PMID: 28826004

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Project description:Hormesis is a dose response phenomenon characterized by a stimulation of an organismal response at low doses of a chemical and inhibition of the response (toxicity) at a higher dose. In the present study, Daphnia magna were exposed to the energetic compound 2,4,6-trinitrotoluene (TNT) for 21 days, and the endpoints survival, growth (length and dry weight), and reproduction (number of neonates per survivor) were assesed, identifying hormetic responses at the lower treatment levels. In order to elucidate the mechanisms leading to hormesis, microarray analysis was performed at 0.004 (hormetic), 0.12 (sometimes hormetic), and 1.85 (toxic) mg/L TNT. Functional and transcriptional benchmark dose analyses performed on differentially expressed genes suggested the involvement of lipid metabolism in hormetic responses and subsequently lipidomic analysis was performed on the same treatments. Lipid analysis supported the hypothesis that TNT exposure affected lipid metabolism, and showed that hormetic effects could be related to increases in some polyunsaturated fatty acids and ecosanoids known to be involved in Daphnia growth and reproduction. Chronic toxicity tests was designed to identify the hormetic range of D. magna responses to TNT. Daphnia magna younger than 24 h old and obtained from in-house cultures at the U.S. Army Engineer Research and Development Center, Environmental Laboratory (Vicksburg, MS) were used to initiate the bioassay. The experimental design consisted of one D. magna per test chamber and 10 test chambers per treatment level. In the microarray mass exposure, nominal treatment levels were 0.004, 0.02, 0.12, 0.44, and 1.85 mg/L. Based on the results of the testing in the 50 ml beakers, organisms from three treatments were selected for analysis of gene expression: 0.004, 0.12, and 1.85 mg/L. These treatments were selected to represent a hormetic concentration (0.004 mg/L), a toxic concentration (1.85 mg/L), and an intermediate concentration (0.12 mg/L). A total of 23 arrays used, with 5-6 replicates per each dose (solvent control, 0.004 mg/L, 0.12 mg/L, and 1.85 mg/L).

Project description:ObjectiveThis study assessed longitudinal changes in body composition, fat distribution and energy balance in perimenopausal women. We hypothesized that total fat and abdominal body fat would increase at menopause due to decreased energy expenditure (EE) and declining estrogen, respectively.DesignObservational, longitudinal study with annual measurements for 4 years.SubjectsHealthy women (103 Caucasian; 53 African-American), initially premenopausal. During follow-up, lack of menstruation for 1 year and follicle-stimulating hormone >30 mIU ml(-1) defined a subject as postmenopausal.MeasurementsFat and lean mass (dual-energy X-ray absorptiometry), visceral (VAT) and subcutaneous abdominal fat (SAT) (computed tomography), dietary intake (4-day food record), serum sex hormones and physical activity (tri-axial accelerometry). Twenty-four hour EE was measured by whole-room calorimeter in a subset of 34 women at baseline and at year 4.ResultsBody fat and weight increased significantly over time only in those women who became postmenopausal by year 4 (n=51). All women gained SAT over time; however, only those who became postmenopausal had a significant increase in VAT. The postmenopausal group also exhibited a significant decrease in serum estradiol. Physical activity decreased significantly 2 years before menopause and remained low. Dietary energy, protein, carbohydrate and fiber intake were significantly higher 3-4 years before the onset of menopause compared with menopause onset. Twenty-four hour EE and sleeping EE decreased significantly with age; however, the decrease in sleeping EE was 1.5-fold greater in women who became postmenopausal compared with premenopausal controls (-7.9 vs -5.3%). Fat oxidation decreased by 32% in women who became postmenopausal (P<0.05), but did not change in those who remained premenopausal.ConclusionMiddle-aged women gained SAT with age, whereas menopause per se was associated with an increase in total body fat and VAT. Menopause onset is associated with decreased EE and fat oxidation that can predispose to obesity if lifestyle changes are not made.

Dataset Information

Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.

Publications

Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.

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