Actions of 17β-estradiol and testosterone in the mitochondria and their implications in aging

Highlights

• 17β-Estradiol and testosterone actions in mitochondria.

• Decline in mitochondrial functions and aging.

• Mitochondrial localization of estrogens and androgens receptors, role in apoptosis.

Abstract

A decline in the mitochondrial functions and aging are two closely related processes. The presence of estrogen and androgen receptors and hormone-responsive elements in the mitochondria represents the starting point for the investigation of the effects of 17β-estradiol and testosterone on the mitochondrial functions and their relationships with aging. Both steroids trigger a complex molecular mechanism that involves crosstalk between the mitochondria, nucleus, and plasma membrane, and the cytoskeleton plays a key role in these interactions. The result of this signaling is mitochondrial protection. Therefore, the molecular components of the pathways activated by the sexual steroids could represent targets for anti-aging therapies. In this review, we discuss previous studies that describe the estrogen- and testosterone-dependent actions on the mitochondrial processes implicated in aging.

Introduction

At the molecular level, the aging process implies a gradual and progressive deterioration of biomolecules to yield a variety of pathological outcomes, such as cancer, neurodegenerative diseases, sarcopenia, and liver dysfunction (Chung et al., 2008, Chung et al., 2009, Seo et al., 2006). Of the various hypotheses that have been proposed to explain the age-related decline in physiological functions, the free radical theory proposed by Harman (1956) and later refined by Miquel et al. (1980) has been extensively studied and is the most enduring. This theory suggests that reactive oxygen species (ROS) from the mitochondria are the major contributors to the injury of biological macromolecules and lead to irreversible cell damage (Kowaltowski et al., 2009 and references therein; Harman, 1956). Because the main source of ROS is mitochondrial respiration, the mitochondria are thought to be the primary target of oxidative damage (Sastre et al., 1996, Miquel et al., 1980). As a result, the mitochondrial genome, ATP production, structure of the organelle, induction/regulation of apoptosis, and other functions are affected by chronic exposure to mitochondrial ROS during aging (Wallace, 2005). Moreover, because the mitochondrial morphology changes with age, an increased volume and fewer cristae have been observed in this organelle in older cells (Wilson and Franks, 1975, Ozawa, 1997). Although the mechanism responsible for this change is not fully understood, the enlargement of the mitochondria with age is another age-dependent alteration of the organelle. Oxidative stress and subsequent mitochondrial swelling appears to be responsible for this phenomenon (Terman et al., 2003). In fact, H₂O₂ induces changes in the morphology and localization of the mitochondria in C2C12 muscle cells, which become pyknotic and grouped near the nucleus (Vasconsuelo et al., 2008). This displacement of the organelle could facilitate the translocation of mitochondrial proteins, such as apoptosis-inducing factor (AIF), which binds to DNA and triggers its destruction, to the nucleus (Susin et al., 2000). Hence, the decrease in the mitochondrial size could be due to a loss of proteins. Because the percentage of distorted components in the mitochondria is augmented by the action of ROS, the mitochondrial capacity to generate energy decreases, and the ROS production and the cellular propensity for apoptosis increases. As these cells gradually die, the tissue function worsens. Clinical symptoms appear when the number of cells in a tissue decreases below the minimum number required to maintain tissue function (Wallace and Lott, 2002). This deleterious effect is more evident in postmitotic tissues with high-energy requirements, such as the heart, brain, and skeletal muscle (Ojaimi et al., 1999, Trounce et al., 1989, Cooper et al., 1992). For instance, histochemical and molecular assays of the human skeletal muscle of healthy subjects aged 13–90 years have clearly shown phenotypic and genotypic alterations associated with aging. The data in this study demonstrated changes in the mitochondria of human skeletal muscle beginning at 40–50 years of age (Pesce et al., 2001). Coincidentally, changes in the sexual hormonal state of individuals also start at this age interval (Lamberts et al., 1997), which suggests a relationship between hormonal levels and mitochondrial status. In women, the abrupt decrease in estradiol at the beginning of menopause leads to a series of physical and emotional symptoms and an increased risk of cardiovascular diseases, sarcopenia, osteoporosis, and dementia (Burger et al., 2002), and these changes are associated with increased ROS production (Harman, 1956, Miquel et al., 1980). Of importance, it has been shown that estrogen is able to overcome these symptoms through its effects on the mitochondria (Viña et al., 2005). For example, 17β-estradiol (E2) plays a direct role in cardiac myocytes. It has been shown that ovariectomy increases cardiomyocyte apoptosis and induces proapoptotic changes in the Bcl-2 and Bax genes and proteins that directly affect the mitochondria (Fabris et al., 2011). Nevertheless, in addition to the mitochondria, other targets of E2, such as lipids, have been described in association with hormone cardiovascular protection. E2 leads to decreased LDL and increased HDL (Liu et al., 2008).

In contrast, the decrease in testosterone (T) production by the testes is progressive (Van den Beld and Lamberts, 2002). The level of circulating testosterone diminishes not only in men with progressing age but also in women because of the age-dependent decrease in ovarian and adrenal androgen production. As expected, these variations in the hormone levels affect the normal functioning of the body, and one way of achieving this effect may involve the mitochondria. Moreover, in view of the fundamental role of the mitochondria in the aging process, these organelles represent putative targets of anti-aging strategies. Thus, the aging-dependent impairment of many physiological functions that usually trigger diseases could be overcome by specifically protecting the molecular components of the mitochondria that are primarily affected by ROS. However, the relationship between ROS-induced damage, mitochondrial function, the regulators involved in the aging process, and their hormonal regulation are far from being elucidated. In this context, we discuss the effects of estrogen and testosterone on the functions of the mitochondria and their possible implications in the elderly.