Oestrogenic Regulation of Mitochondrial Dynamics

Abstract

Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion-fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.

Keywords: 17β-oestradiol; biological sex; cardiovascular; heart–brain axis; neuronal.

Figure 1

E2 regulation of mitochondrial function and turnover. Several signalling proteins contribute to the effects of E2 on mitochondrial respiration, biogenesis, mitophagy and cell death. Abbreviations: Aif1: Apoptotic-inducing factor 1, E2: 17β-Oestradiol, ERα: oestrogen receptor α, ERβ: oestrogen receptor β, Erk: extracellular signal-regulated kinase, Mapk: mitogen-activated-protein-kinase, MPTP: mitochondria permeability transition pore, Nfκb: Nuclear factor kappa-light-chain-enhancer of activated B cells, Nrf1: nuclear receptor factor, Pgc-1α: proliferator-activated receptor-γ coactivator 1-α, Pgc-1β: proliferator-activated receptor-γ coactivator 1-β, PI3K: phosphatidylinositol-3-OH kinase, Sp1: stimulating protein-1 and Tfam: mitochondrial transcription factor A.

Figure 2

Effects of E2 on mitochondrial dynamics in the cardiovascular system. E2–ERβ interaction modulates the proteins of mitochondrial dynamics in a direct or indirect manner, thereby eliciting effects on cardiovascular (patho)physiology. Abbreviations: Drp1: dynamin-related protein 1, E2: 17β-Oestradiol, ERβ: oestrogen receptor β, Erk: extracellular signal-regulated kinase, Fis1: fission factor 1, INR: insulin resistance, IRI: ischaemia-reperfusion injury, Mapk: mitogen-activated-protein-kinase, Mfn1: mitofusin 1, Mfn2: mitofusin 2, MPTP: mitochondria permeability transition pore, Opa1: optic atrophy 1, PI3K: phosphatidylinositol-3-OH kinase, Phb: prohibitin and ROS: reactive oxygen species.

Figure 3

Effects of E2 on mitochondrial dynamics in pathologies of the nervous system. E2-associated signalling via its receptors or drugs that promote E2 production lead to the attenuation of fission and the promotion of fusion. Abbreviations: Aβ: amyloid-beta protein, Akap1: activates kinase anchoring protein 1, Drp1: dynamin-related protein 1, E2: 17β-Oestradiol, ERβ: oestrogen receptor β, Fis1: fission factor 1, Mfn1: mitofusin 1, Mfn2: mitofusin 2, MPTP: mitochondria permeability transition pore, Opa1: optic atrophy 1, Pka: protein kinase A and Sod: sodium oxide dismutase.

Figure 4

The significance of E2 regulation of mitochondrial dynamics in the heart–brain axis (HBA). Current literature points towards the attenuating effects of E2 on mitochondrial fission. In particular, Drp1 inhibition is involved in the effects of E2 in HBA, as the absence of E2 leads to increased fission or decreased fusion. These alterations then promote cardiovascular diseases that are linked to Alzheimer’s disease. On the other hand, the presence of E2 may potentially inhibit the fission activity of Drp1 to prevent cardiovascular diseases that stem from neurological pathologies.