1. Melatonin enhances SIRT1 to ameliorate mitochondrial membrane damage by activating PDK1/Akt in granulosa cells of PCOS.
- Author
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Zheng B, Meng J, Zhu Y, Ding M, Zhang Y, and Zhou J
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases metabolism, Adult, Animals, Benzimidazoles metabolism, Carbocyanines metabolism, Cytochromes c drug effects, Cytochromes c metabolism, Cytoplasm drug effects, Cytoplasm metabolism, Female, Gene Knockdown Techniques, Granulosa Cells metabolism, Granulosa Cells ultrastructure, Humans, Membrane Potential, Mitochondrial drug effects, Mice, Mitochondria metabolism, Mitochondrial Membranes drug effects, Mitochondrial Membranes metabolism, Mitochondrial Permeability Transition Pore metabolism, Proto-Oncogene Proteins c-akt drug effects, Proto-Oncogene Proteins c-akt metabolism, Sirtuin 1 genetics, Sirtuin 1 metabolism, bcl-2-Associated X Protein drug effects, bcl-2-Associated X Protein metabolism, 3-Phosphoinositide-Dependent Protein Kinases drug effects, Granulosa Cells drug effects, Melatonin pharmacology, Mitochondria drug effects, Polycystic Ovary Syndrome metabolism, Sirtuin 1 drug effects
- 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., (© 2021. The Author(s).)
- Published
- 2021
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