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SOD2 deficiency-induced oxidative stress attenuates steroidogenesis in mouse ovarian granulosa cells
Syed Kashif Zaidi1, Wen-Jun Shen1, Yuan Cortez2
1Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Abstract:
This study investigated the effects of SOD2 (MnSOD)-deficiency-induced excessive oxidative stress on ovarian steroidogenesis in vivo and isolated and cultured granulosa cells using WT and Sod2+/- mice. Basal and 48 h eCG-stimulated plasma progesterone levels were decreased ~50% in female Sod2+/- mice, whereas plasma progesterone levels were decreased ~70% in Sod2+/- mice after sequential stimulation with eCG followed by hCG. Sod2+/- deficiency caused about 50% reduction in SOD2 activity in granulosa cells. SOD2-deficiency also caused a marked reduction in progestins and estradiol in isolated granulosa cells. qRT-PCR measurements indicated that the mRNA expression levels of StAR protein and steroidogenic enzymes are decreased in the ovaries of Sod2+/- mice. Further studies showed a defect in the movement of mobilized cytosolic cholesterol to mitochondria. The ovarian membrane from Sod2+/- mice showed higher susceptibility to lipid peroxidation. These data indicates that SOD2-deficiency induced oxidative stress inhibits ovarian granulosa cell steroidogenesis primarily by interfering with cholesterol transport to mitochondria and attenuating the expression of Star protein gene and key steroidogenic enzyme genes.
Insights
SOD2 deficiency causes oxidative stress, impairing ovarian steroidogenesis. This leads to reduced progesterone and estradiol by affecting cholesterol transport and steroidogenic gene expression in granulosa cells.
Area of Science:
- Reproductive Biology
- Oxidative Stress Research
- Mitochondrial Function
Background:
- Oxidative stress is implicated in reproductive dysfunction.
- Superoxide dismutase 2 (SOD2/MnSOD) is a key mitochondrial antioxidant enzyme.
- The role of SOD2 in ovarian steroidogenesis under oxidative stress is not fully understood.
Purpose of the Study:
- To investigate the impact of SOD2 deficiency-induced oxidative stress on ovarian steroidogenesis.
- To elucidate the mechanisms by which SOD2 deficiency affects granulosa cell function and steroid production.
Main Methods:
- Utilized wild-type (WT) and Sod2+/- mice to model SOD2 deficiency.
- Assessed plasma progesterone and estradiol levels in vivo following hormonal stimulation (eCG, hCG).
- Analyzed SOD2 activity, steroid hormone production, and gene expression (StAR, steroidogenic enzymes) in isolated granulosa cells and ovarian tissues.
Main Results:
- Sod2+/- mice exhibited significantly reduced basal and stimulated plasma progesterone levels.
- Granulosa cells from Sod2+/- mice showed decreased SOD2 activity, progestin, and estradiol production.
- SOD2 deficiency led to reduced mRNA expression of StAR and key steroidogenic enzymes, and impaired cholesterol transport to mitochondria.
- Ovarian membranes from Sod2+/- mice displayed increased susceptibility to lipid peroxidation.
Conclusions:
- SOD2 deficiency-induced oxidative stress significantly inhibits ovarian steroidogenesis.
- The primary mechanisms involve impaired cholesterol transport to mitochondria and reduced expression of StAR and steroidogenic enzyme genes.
- SOD2 plays a critical role in protecting ovarian granulosa cells from oxidative damage and maintaining steroidogenic function.
