Abstract

Mitochondrial injury in granulosa cells (GCs) is associated with the pathophysiological mechanism of polycystic ovary syndrome (PCOS). Melatonin reduces the mitochondrial injury by enhancing SIRT1 (NAD-dependent deacetylase sirtuin-1), while the mechanism remains unclear. Mitochondrial membrane potential is a universal selective indicator of mitochondrial function. In this study, mitochondrial swelling and membrane defect mitochondria in granulosa cells were observed from PCOS patients and DHT-induced PCOS-like mice, and the cytochrome C level in the cytoplasm and the expression of BAX (BCL2-associated X protein) in mitochondria were significantly increased in GCs, with p-Akt decreased, showing mitochondrial membrane was damaged in GCs of PCOS. Melatonin treatment decreased mitochondrial permeability transition pore (mPTP) opening and increased the JC-1 (5,5′,6,6′-tetrachloro1,1′,3,3′-tetramethylbenzimidazolylcarbocyanine iodide) aggregate/monomer ratio in the live KGN cells treated with DHT, indicating melatonin mediates mPTP to increase mitochondrial membrane potential. Furthermore, we found melatonin decreased the levels of cytochrome C and BAX in DHT-induced PCOS mice. PDK1/Akt played an essential role in improving the mitochondrial membrane function, and melatonin treatment increased p-PDK 1 and p-Akt in vivo and in vitro. The SIRT1 was also increased with melatonin treatment, while knocking down SIRT1 mRNA inhibiting the protective effect of melatonin to activate PDK1/Akt. In conclusion, melatonin enhances SIRT1 to ameliorate mitochondrial membrane damage by activating PDK1/Akt in granulosa cells of PCOS.

Highlights

  • Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting reproductive age women [1,2,3,4]

  • Reproductive Medicine Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Zhongshan Road 32, Nanjing 210008, China in granulosa cells of PCOS patients was lower than the control group; the expression of OXPHOS-related genes was down-regulated in PCOS patients [7, 8], which indicated that mitochondrial injury in Granulosa cells (GCs) is associated with the pathogenesis of PCOS

  • Protein Kinase B (Akt) activation played a vital role in maintaining the mitochondrial membrane permeabilization (MMP), while the p-Akt level in GCs was decreased in PCOS patients (Fig. 1B-D, n = 6 for each group)

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Summary

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting reproductive age women [1,2,3,4]. Excessive clinical or biochemical levels of androgen, ovulatory dysfunction, and polycystic ovarian morphology are recognized as the main characteristics of PCOS [5, 6]. Granulosa cells (GCs) play a vital role in hormonesecreting and follicle development and maturation [2]. Studies showed that the content of mtDNA (mitochondrial DNA) in granulosa cells of PCOS patients was lower than the control group; the expression of OXPHOS-related genes was down-regulated in PCOS patients [7, 8], which indicated that mitochondrial injury in GCs is associated with the pathogenesis of PCOS. The mechanism of mitochondrial injury in PCOS remains unclear. Some studies showed mitochondrial injury might be associated with excessive oxidative stress [5, 7]. Study showed that mitochondrial membrane potential is a universal selective indicator of mitochondrial function, and is essential for mitochondrial ability to maintain a balanced metabolic micro-environment [9], indicating that mitochondrial membrane

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