**Estrogen and Mitochondrial Function in Disease**

**Estrogen and Mitochondrial Function in Disease**

DOI: 10.5772/intechopen.73015

#### Ved P. Mooga, C. Roger White and Samantha Giordano-Mooga Samantha Giordano-Mooga Additional information is available at the end of the chapter

Ved P. Mooga, C. Roger White and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73015

#### **Abstract**

Anecdotal and scientific evidence suggest that the sex hormone estrogen provides significant health benefits in women. Women have higher estrogen levels than men. Circulating estrogen reaches its highest level during the reproductive period and steadily declines with the onset of menopause. The role of estrogen and estrogen receptors in both cellular physiology and pathophysiology has been controversial. Estrogen has anti-inflammatory and anti-oxidant effects, which preserve cell viability during cardiovascular incidents, but it enhances disease progression in the context of breast cancer. Estrogen mediates these responses *via* activation of estrogen receptor subtypes located in the cell membrane, nucleus, and mitochondrion. Further, transcription of nuclear and mitochondrial genes by estrogen yields products that play an important role in regulating mitochondrial function. Mitochondria are part of a highly dynamic network and undergo fission and fusion, produce cellular energy, adenosine 5′ triphosphate (ATP), and regulate cell death. Herein, we review the cell and receptor specific effects of estrogen on mitochondrial structure, function, and cell death under normal physiological conditions and in the context of cardiovascular disease, inflammation, neurodegeneration, and cancer. Further research is needed to elucidate the specific role of estrogenic control of mitochondria in health and disease.

**Keywords:** estrogen, mitochondria, aging, menopause, estrogen receptors

#### **1. Introduction**

The term estrogen refers to a family of chemically similar steroid hormones that include estrone, estradiol, and estriol. Estrogens are synthesized primarily by the ovarian follicles [1]. An important rate limiting step in steroid hormone synthesis is the production of pregnenolone in follicular granulosa cells. Cholesterol is transported from the outer to the inner mitochondrial membrane by the steroidogenic acute regulatory (StAR) protein, followed

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

by conversion to pregnenolone by cytochrome P450 side chain cleavage (CYP11A1). Pregnenolone then diffuses to the theca cells where it is converted to androstenedione and then re-routed to the granulosa cells for the aromatase-mediated conversion to estrogen. Androstenedione can also be converted to testosterone. Thus, mitochondria play an important role in estrogen biosynthesis.

Studies utilizing ERα and ERβ knockout (KO) mice have provided insight into the function of each receptor type. Male and female ERα KO mice are infertile, while ERβ KO mice are fertile but produce small litters [12–14]. These studies highlight the importance of estrogen in the

Estrogen and Mitochondrial Function in Disease http://dx.doi.org/10.5772/intechopen.73015 465

ERα and ERβ are also found on the membranes of cellular organelles, including the endoplasmic reticulum and the mitochondrion, where they mediate various cellular functions. Localization to mitochondria was first confirmed using radioligand binding methods in mitochondria isolated from rat uterus and later by immunocytochemistry in rat pancreatic acinar cells [16]. MALDI-TOF mass spectrometry studies have shown that mitochondrial ERs are identical to ERs located in the nucleus [17]. ERβ is the predominant mitochondrial receptor in most tissues: for example ovary, uterus, spermatocytes, cerebral and hippocampal neurons, cardiomyocytes, and endothelial cells [17, 18]. In contrast, the identification of mitochondrial ERα has been limited to the uterus, ovary, and the MCF-7 breast cancer cell line [18]. The presence of ERs on mitochondria and estrogen responsive elements on the mitochondrial DNA suggests a role for estrogen in regulating the structure and/or function

Estrogen also binds to a GPER on the plasma membrane. GPER specifically binds to estradiol and mediates numerous responses including cell proliferation, vasodilation, and regulation of glucose metabolism by non-genomic mechanisms [20]. GPER has also been localized to intracellular sites. In the endoplasmic reticulum, GPER activation induces calcium release and activation of the phosphoinositide 3-kinase (PI3K)-*Akt* pathway, which induces cell proliferation [21, 22]. While GPER is not associated with the mitochondria, its regulation of cellular calcium handling indirectly impacts mitochondrial function and mitochondrial-induced cell death [22, 23]. Calcium uptake by mitochondria results in the opening of the mitochondrial permeability transition pore (mPTP) and induction of the intrinsic cell death pathway. GPERspecific agonist G1 binding to GPER has been shown to attenuate these responses in a rodent model of ischemia/reperfusion (I/R) by preventing endoplasmic reticulum calcium release [23]. ER-X is an additional estrogen receptor type that is associated with the cell membrane. This novel receptor shares sequence homology with ERα and ERβ, which is expressed primarily in the brain during development and becomes re-expressed in response to ischemic brain injury [24]. While little is known regarding the function of ER-X, some data suggest that

The mitochondria are classically described as the powerhouse of the cell by virtue of its ability to generate ATP. Physiological processes underlying mitochondrial bioenergetics and respiration have been previously reviewed [25]. Under aerobic conditions, mitochondria utilize electron transport and a protomotive force to produce ~36 ATP molecules for every glucose molecule. Reducing equivalents produced by the Krebs cycle (NADH and FADH<sup>2</sup>

are accepted by the respiratory chain at Complex I (NADH Dehydrogenase) and Complex

)

development of reproductive systems of both sexes [14, 15].

of the organelle [19].

it exerts a cytoprotective role in the brain [24].

**3. Mitochondrial function**

Estrogen serves a major role in determining female secondary sex characteristics during development and in regulating the estrous cycle. During puberty and throughout the female reproductive cycle, estrogen levels fluctuate, and as women age, sex steroid production decreases [1]. Estrogen levels oscillate during the estrous cycle. They are lowest during menstruation, steadily rise during the follicular stage and reach a maximal level during ovulation. If a woman becomes pregnant, estrogen levels will remain high, but if fertilization does not occur, hormone levels decline during the luteal phase. Following the luteal phase, menstruation occurs, and the cycle resumes. As estrogen levels fluctuate during the estrous cycle, mitochondria alter the production of pregnenolone accordingly.

Estrogen is a pleiotropic hormone that exerts its effects *via* both transcriptional and nongenomic mechanisms. In addition to regulating reproductive function, estrogen exerts numerous cytoprotective effects. With respect to atherosclerosis, estrogen regulates levels of circulating lipids by stimulating the formation of high density lipoprotein (HDL) and decreasing expression of low density lipoprotein (LDL) [2]. It exerts antioxidant and anti-inflammatory effects by preventing the oxidation of LDL, inhibiting the expression of endothelial cell adhesion molecules and stimulating nitric oxide formation [3]. As discussed in this chapter, differential responses to estrogen are due to activation of different receptor subtypes. Recent studies also suggest that many of the protective responses to estrogen are related to the ability of the hormone to maintain normal mitochondrial function. Mitochondrial localization of estrogen receptors has been shown to regulate mitochondrial gene expression. In this manner, estrogen plays an important role in the supporting mitochondrial respiration and adenosine 5′ triphosphate (ATP) production, reducing reactive oxygen species (ROS) formation and inhibiting activation of mitochondrial cell death pathways. The goal of this chapter is to discuss mechanisms by which estrogen regulates mitochondrial signaling and function under normal physiological conditions and in the context of disease.
