Page 17 - GTM-3-3

Global Translational Medicine Influence of estrogen on RV mitochondria in PH

6.3. NRF1/2 E2 and its role in regulating RV mitochondrial function in

To date, two members of the NRF family have been PAH are required.
identified: NRF1 and several isoforms of NRF2, also 6.5. ERK1/2 (MAPK)
known as GA-binding protein (GABPA). The NRF family
has been shown to be activated by PGC-1α and once When E2 binds to the plasma membrane GPER (also
94,95
activated, targets several genes related to mitochondria and known as GPR30), it activates Gα, Gβ, and Gγ subunits,
respiration. 89,90 Once activated, for instance by PGC-1α, which then stimulates cAMP and cyclic guanosine
95
NRF1 and NRF2 will then bind to three key mitochondrial monophosphate (cGMP) production. The production
transcription factors, TFAM, mitochondrial transcription of cAMP and cGMP activates several signaling pathways
factor B1 (TFB1M), and mitochondrial transcription including the indirect activation of calcium. 94-96 The
2+
factor B2 (TFB2M) to promote upregulation of their intracellular Ca release is thought to be one of the main
68
expression. These three transcription factors can then mechanisms by which GPER influences the mitochondria.
90
be translocated to the mitochondria to induce mtDNA In addition, the major kinase enzyme family activated
replication, transcription, and hence, biogenesis. Mutation through the GPER, MAPK, and one of its subfamilies
in the NRF1 binding site has been shown to completely ERK1/2 play a key role in regulating proliferation in
97
abolish the activation of TFAM, with mutations in the response to oxidants, hormones, and stress factors, hence
NRF2 binding site shown to only dampen TFAM activity. 91 influencing mitochondrial function in PAH. 98
The role of the NRF family is just beginning to be Although the data on ERK1/2 in RV in PAH is limited,
understood in PAH. One study illustrated that NRF1 there are few studies on the lungs in PAH. ERK1/2 levels are
mRNA expression showed no changes in the RV of male significantly elevated in the lungs of human PAH patients
97
MCT rats. Another study found an increased NRF1 in the (40% male and 60% female) and in hypoxic male rats.
85
RV of male rats following 14 days in hypoxia. Since chronic There is also an increase in ERK1/2 phosphorylation in the
92
hypoxia alone only results in an adaptive or compensated pulmonary arteries of male MCT rats. 28,99 An increase in
RV, the reason for this increased NRF1 in hypoxic rats ERK1/1 was found to stimulate dynamin-related protein
could be due to positive feedback in the RV to prevent RV 1 (DRP1), resulting in excess mitochondrial fission and
99
failure as the NRFs mediate protective effects. Given the proliferation in PASMCs of male MCT rats. An ERK
potential role of the NRF family in mitochondrial function
and its sex dependence (Figure 2), it is worth studying the Table 2. List of mitochondria and estrogen‑related genes
NRF family as potential therapeutic targets. and their changes in the right ventricle (RV) in pulmonary
arterial hypertension (PAH)
6.4. TFAM
Genes Protein/mRNA expression in RV in PAH References
TFAM binds to the D-loop of mtDNA whereby it initiates PGC‑1α • Downregulated in male SuHx Sprague‑Dawley 84,85
activation of mitochondrial replication and transcription. rats 84
It is the key enhancer that promotes the unwinding of • Downregulated in male MCT Wistar rats 85
the mitochondrial RNA to allow for mitochondrial RNA • A decreasing trend in human PAH patients 84
polymerase (POLRMT) to bind to mtDNA promoters to NRF2 Unknown
be transcribed. Ultimately, TFAM is deemed essential for ERK Unknown
90
increasing mitochondrial mass. Although, the previous NRF1 • Downregulated in male MCT Wistar rats 85
studies have indicated that despite its ability to stimulate TFAM • Downregulated in male SuHx Sprague‑Dawley 84,85
mtDNA transcription, it is not able to do so for mtDNA rats 84
copy number. Moreover, they reported that excessive • Downregulated in male MCT Wistar rats 85
93
TFAM concentration can also lead to an inhibition effect GPER • No change in male and female SuHx 29
on the transfection rate. 93 Sprague-Dawley rats
Investigations into TFAM in PAH are limited and even ERα • No change in male and female SuHx 29
more so in the context of the RV. The mRNA expression Sprague-Dawley rats
of TFAM was found to decrease in RV of male SuHx ERβ • No change in male and female SuHx 29
and male Wistar MCT rats but not male PAB rats. 84,85 Sprague-Dawley rats
In compensated male MCT rats, mRNA expression of Abbreviations: SuHx: Sugen/hypoxia; MCT: Monocrotaline;
TFAM had a decreasing trend in RV. This suggests that PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator;
85
TFAM: Mitochondrial transcription factor A; GPER: G protein-coupled
the reduction in TFAM is independent of RV pressure estrogen receptor 1; ER: Estrogen receptor; NRF: Nuclear respiratory
overload. Further studies on how TFAM is regulated by factor; ERK: Extracellular signal-regulated kinase.

Volume 3 Issue 3 (2024) 7 doi: 10.36922/gtm.2494