Methylglyoxal-Dependent Glycative Stress and Deregulation of SIRT1 Functional Network in the Ovary of PCOS Mice.

Giovanna Di Emidio,Maria Grazia Palmerini,Giulia Rossi,Martina Placidi,Carla Tatone,Fernanda Amicarelli,Stefania Nottola,Stefano Falone,Loredana Cristiano,Francesco Rea,Anna Maria D’Alessandro

doi:10.3390/cells9010209

Giovanna Di Emidio, Maria Grazia Palmerini + Show 9 more

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https://doi.org/10.3390/cells9010209

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Journal: Cells	Publication Date: Jan 14, 2020
Citations: 20	License type: CC BY 4.0

Affiliation: University of L'Aquila

Abstract

Advanced glycation end-products (AGEs) are involved in the pathogenesis and consequences of polycystic ovary syndrome (PCOS), a complex metabolic disorder associated with female infertility. The most powerful AGE precursor is methylglyoxal (MG), a byproduct of glycolysis, that is detoxified by the glyoxalase system. By using a PCOS mouse model induced by administration of dehydroepiandrosterone (DHEA), we investigated whether MG-dependent glycative stress contributes to ovarian PCOS phenotype and explored changes in the Sirtuin 1 (SIRT1) functional network regulating mitochondrial functions and cell survival. In addition to anovulation and reduced oocyte quality, DHEA ovaries revealed altered collagen deposition, increased vascularization, lipid droplets accumulation and altered steroidogenesis. Here we observed increased intraovarian MG-AGE levels in association with enhanced expression of receptor for AGEs (RAGEs) and deregulation of the glyoxalase system, hallmarks of glycative stress. Moreover, DHEA mice exhibited enhanced ovarian expression of SIRT1 along with increased protein levels of SIRT3 and superoxide dismutase 2 (SOD2), and decreased peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1α), mitochondrial transcriptional factor A (mtTFA) and translocase of outer mitochondrial membrane 20 (TOMM20). Finally, the presence of autophagy protein markers and increased AMP-activated protein kinase (AMPK) suggested the involvement of SIRT1/AMPK axis in autophagy activation. Overall, present findings demonstrate that MG-dependent glycative stress is involved in ovarian dysfunctions associated to PCOS and support the hypothesis of a SIRT1-dependent adaptive response.

Highlights

Polycystic ovarian syndrome (PCOS) is a common and complex endocrine disorder affecting4–21% of women in reproductive age [1,2]
From a wide medullar stroma, rich of blood vessels embedded in a loose collagenous matrix, numerous sepiments protruded in the cortex to partially detach ovarian follicles and corpora lutea
It has emerged that overload of advanced glycation end products (AGEs) is a key factor in ovarian dysfunctions and reduced fertility associated with polycystic ovary syndrome (PCOS)

Summary

Introduction

Polycystic ovarian syndrome (PCOS) is a common and complex endocrine disorder affecting4–21% of women in reproductive age [1,2]. Polycystic ovarian syndrome (PCOS) is a common and complex endocrine disorder affecting. According to the Rotterdam criteria, the PCOS classic phenotype consists of hyperandrogenism, oligo-ovulation and polycystic ovaries, in association with insulin resistance, metabolic disorders and infertility [3]. New players have been implicated in the pathogenesis of PCOS, the advanced glycation end products (AGEs). Glycation is a spontaneous non-enzymatic reaction of reducing sugars with free amino groups of proteins, DNA and lipids that forms Amadori products. The Amadori products undergo a variety of irreversible dehydration and rearrangement reactions that lead to the formation of AGEs [6]. The most powerful precursor of AGEs is methylglyoxal (MG), a low-molecular weight dicarbonyl compound derived from metabolic processes [7]. Intracellular MG detoxification relies on the activity of the so-called glyoxalase system, composed of glyoxalase 1 (GLO1) and glyoxalase 2 (GLO2)

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