X-rays and metformin cause increased urinary excretion of cell-free nuclear and mitochondrial DNA in aged rats

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Abstract

Activation of cell death in mammals can be assessed by an increase of an amount of cell-free DNA (cf-DNA) in urine or plasma. We investigated the excretion of cf nuclear DNA (nDNA) and cf mitochondrial DNA (mtDNA) in the urine of rats 3 and 24 months in age after X-irradiation and metformin administration. Analyses showed that prior to treatment, the amount of cf-nDNA was 40% higher and cf-mtDNA was 50% higher in the urine of aged rats compared to that of young animals. At 12 h after irradiation, the content of cf-nDNA and cf-mtDNA in the urine of young rats was increased by 200% and 460%, respectively, relative to the control, whereas in the urine of aged rats, it was 250% and 720% higher. After 6 h following metformin administration, the amount of cf-nDNA and cf-mtDNA in the urine of young rats was elevated by 25% and 55% and by 50% and 160% in the urine of aged rats. Thus, these preliminary data suggest that X-rays and metformin cause a significant increase of cf-DNA in the urine of older rats caused by the active cell death in tissues. These results also suggest that metformin possibly initiates the death of the cells containing structural and functional abnormalities.

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Most cited references 38

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Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

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Author and article information

Journal

Journal ID (nlm-ta): J Circ Biomark

Journal ID (iso-abbrev): J Circ Biomark

Journal ID (publisher-id): CBX

Journal ID (hwp): spcbx

Title: Journal of Circulating Biomarkers

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Electronic): 1849-4544

Publication date (Electronic): 25 October 2016

Publication date Collection: Jan-Dec 2016

Volume: 5

Electronic Location Identifier: 1849454416670782

Affiliations

[1-1849454416670782]Institute of Theoretical and Experimental Biophysics, RAS, Pushino, Moscow Region, Russia

Author notes

[*]Azhub Gaziev, Institute of Theoretical and Experimental Biophysics, RAS, 142290 Pushino, Moscow Region, Russia. Email: gaziev.iteb@ 123456gmail.com

Article

Publisher ID: 10.1177_1849454416670782

DOI: 10.1177/1849454416670782

PMC ID: 5548319

SO-VID: 060759e3-09a6-4286-b74a-7f96fff0fa85

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).