Estrogens, Estrogen Receptors Effects on Cardiac and Skeletal Muscle Mitochondria

Abstract

Mitochondria are unique organelles present in almost all cell types. They are involved not only in the supply of energy to the host cell, but also in multiple biochemical and biological processes like calcium homeostasis, production, and regulation of reactive oxygen species (ROS), pH control, or cell death. The importance of mitochondria in cell biology and pathology is increasingly recognized. Being maternally inherited, mitochondria exhibit a tissue-specificity, because most of the mitochondrial proteins are encoded by the nuclear genome. This renders them exquisitely well-adapted to the physiology of the host cell. It is thus not surprising that mitochondria show a sexual dimorphism and that they are also prone to the influence of sex chromosomes and sex hormones. Estrogens affect mitochondria through multiple processes involving membrane and nuclear estrogen receptors (ERs) as well as more direct effects. Moreover, estrogen receptors have been identified within mitochondria. The effects of estrogens on mitochondria comprise protein content and specific activity of mitochondrial proteins, phospholipid content of membranes, oxidant and anti-oxidant capacities, oxidative phosphorylation, and calcium retention capacities. Herein we will briefly review the life cycle and functions of mitochondria, the importance of estrogen receptors and the effects of estrogens on heart and skeletal muscle mitochondria.

Keywords: estrogen receptors; estrogens; heart; mitochondria; sexual dimorphism; skeletal muscle.

Figure 1

Transcription cascade of mitochondrial biogenesis. Increased expression or activity of the master regulators of mitochondrial biogenesis “peroxisome proliferator activator receptor (PPAR) γ co-activators” (PGC-1s) α and β activate the expression of the nuclear respiratory factors 1 and 2 (NRFs) which induce the expression of the mitochondrial transcription factor A (mtTFA). The latter translocates to mitochondria, binds to mtDNA and activates its transcription and replication. PGC-1s also activate other transcription factors such as PPARα, mainly regulating lipid metabolism, estrogen-related receptors (ERRs) involved in substrate metabolism, energy transfer, angiogenesis and detoxification of reactive oxygen species, and the forkhead family of transcription factors (FOXOs) that activate antioxidant and detoxifying proteins.

Figure 2

Estrogen effects in muscle cells. Estradiol (E2) binds to its cytosolic receptors, estrogen-receptor α (ERα) and β (ERβ) inducing the translocation of the complex E2/estrogen receptors (ER) to the nucleus. Interaction of this complex with nuclear DNA results in the transcription of Pgc-1α, Nrfs, and other mitochondrial genes are involved in mitochondrial biogenesis, fatty acid utilization, and antioxidant defenses. Estradiol also interacts with ERs bound to mitochondrial DNA (mtDNA), thereby leading to transcription and replication of the mtDNA. E2 can also bind to G-protein-coupled estrogen receptors (GPER) at the plasma membrane, activating intracellular signaling pathways like extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K), c-Jun-NH2-terminal protein kinase (JNK), and others. This results in the transcription of genes encoding antioxidant enzymes, thus reinforcing in particular the antioxidant defenses of the mitochondria.