Vitamin D3 affects mitochondrial biogenesis through mitogen‐activated protein kinase in polycystic ovary syndrome mouse model

Abstract

Polycystic ovarian syndrome (PCOS) is a disorder characterized by oligomenorrhea, anovulation, and hyperandrogenism. Altered mitochondrial biogenesis can result in hyperandrogenism. The goal of this study was to examine the effect of vitamin D3 on mitochondrial biogenesis of the granulosa cells in the PCOSinduced mouse model. Vitamin D3 applies its effect via the mitogen-activated pathway kinase-extracellular signal-regulated kinases (MAPK-ERK1/2) pathway. The PCOS mouse model was induced by the injection of dehydroepiandrosterone (DHEA). Isolated granulosa cells were subsequently treated with vitamin D3, MAPK activator, and MAPK inhibitor. Gene expression levels were measured using real-time polymerase chain reaction. MAPK proteins were investigated by western blot analysis. We also determined reactive oxygen species (ROS) levels with 2′, 7′-dichlorofluorescein diacetate. Mitochondrial membrane potential (mtMP) was also measured by TMJC1. Mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-α and nuclear respiratory factor), antioxidant (superoxide dismutase, glutathione peroxidase, and catalase), and antiapoptotic (B-cell lymphoma-2) genes were upregulated in the PCOS mice that treated with vitamin D3 compared with the PCOS mice without any treatment. Vitamin D3 and MAPK activator-treated groups also reduced ROS levels compared with the nontreated PCOS group. In summary, vitamin D3 and MAPK activator increased the levels of mitochondrial biogenesis, MAPK pathway, and mtMP markers, while concomitantly decreased ROS levels in granulosa cells of the PCOS-induced mice. This study suggests that vitamin D3 may improve mitochondrial biogenesis through stimulation of the MAPK pathway in cultured granulosa cells of DHEA-induced PCOS mice which yet to be investigated. K E Y W O R D S granulosa cell, MAPK-ERK1/2 pathway, mitochondrial biogenesis, polycystic ovary syndrome, vitamin D3population. The optimal dose of vitamin D3 and the duration of the treatment for clinical trials would be a step forward towards PCOS treatment in women.

β-Sitosterol Ameliorates Endometrium Receptivity in PCOS-Like Mice: The Mediation of Gut Microbiota

“…Many literature have reported that DHEA induced rodent models with remarkable characteristics of polycystic ovary syndrome (30)(31)(32)(33). The reversal of FSH/LH ratio is an important clinical feature of PCOS (34).…”

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

“…Nevertheless, it is known that vitamin D metabolism in PCOS is disrupted and, most probably, contributes to PCOS pathogenesis [105]. Thus, it is not surprising that vitamin D has a direct effect on mitochondria; it improves biogenesis and antiapoptotic parameters and upregulates the expression of antioxidants (SOD, catalase and glutathione peroxidase), which lead to a decrease in ROS levels [106]. Vitamin D treatment stimulates the expression of the TFAM (mitochondrial transcription factor A) gene, the main nuclear regulator of mitochondria biogenesis, leading to a higher copy number of mtDNA and improved membrane integrity [107].…”

Circadian Clock Genes REV-ERBs Inhibits Granulosa Cells Apoptosis by Regulating Mitochondrial Biogenesis and Autophagy in Polycystic Ovary Syndrome

“…Interestingly, a defect in mitochondrial function and biogenesis could lead to consequences such as insulin resistance, hyperandrogenism, oxidative stress and glucose intolerance that are considered as key features in PCOS ( Victor et al, 2009 ; Zhao et al, 2015 ). Additionally, low mitochondrial membrane potential (mtMP) is a critical characteristic that affects the quality of the oocyte thus acting as a key player affecting fertility outcomes ( Safaei et al, 2020 ). Previously, a study has indicated that alterations in the mitochondrial biogenesis levels can give rise to hyperandrogenism and increase in the biogenesis of mitochondria can ameliorate PCOS by decreasing reactive oxygen species in granulosa cells, thus highlighting the potential role of mitochondria in PCOS ( Safaei et al, 2020 ).…”

“…Additionally, low mitochondrial membrane potential (mtMP) is a critical characteristic that affects the quality of the oocyte thus acting as a key player affecting fertility outcomes ( Safaei et al, 2020 ). Previously, a study has indicated that alterations in the mitochondrial biogenesis levels can give rise to hyperandrogenism and increase in the biogenesis of mitochondria can ameliorate PCOS by decreasing reactive oxygen species in granulosa cells, thus highlighting the potential role of mitochondria in PCOS ( Safaei et al, 2020 ). Studies have shown that reduced mitochondrial biosynthesis promotes cell apoptosis ( Diebold et al, 2015 ; Zhang et al, 2017 ; Wood Dos Santos et al, 2018 ).…”