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. 2018 Apr 27;10:124. doi: 10.3389/fnagi.2018.00124

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Copyright © 2018 Lejri, Grimm and Eckert.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Model of possible interactions between estrogen, BDNF and SIRT3. BDNF protein binds to its tyrosine kinase B receptor (TrkB) which stimulates signaling pathways, including the extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K) pathways. This leads to the activation of the cAMP response element-binding protein (CREB) and transcription of genes, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Estrogen (E2) activates similar signaling pathways as BDNF, and, by binding its receptor (ER), modulates the gene expression of BDNF, TrkB and SIRT3. SIRT3 protein translocates to mitochondria and interacts with Forkhead box O3 (FOXO3A), thereby activating this protein. In turn, activated FOXO3A (Act. FOXO3A) induces the transcription of the manganese superoxide dismutase (MnSOD) which acts as ROS scavengers in mitochondria. In addition, SIRT3 protects the cell from ROS directly through the deacetylation of MnSOD. SIRT3 regulates also the expression of PGC-1α (indicated by the doted arrow) which is involved in mitochondrial biogenesis. In the graph, E2 designates where estrogen may interact with the BDNF and SIRT3 pathways. BDNF: brain derived neurotrophic factor, CRE, cAMP response elements, PGC-1α, proliferator-activated receptor gamma coactivator 1-alpha, SIRT3, sirtuin 3.