Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection
Open accessAbstract
We previously found that estrogen exerts a novel protective effect on mitochondria in brain vasculature. Here we demonstrate in rat cerebral blood vessels that 17β-estradiol (estrogen), both in vivo and ex vivo, affects key transcriptional coactivators responsible for mitochondrial regulation. Treatment of ovariectomized rats with estrogen in vivo lowered mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) but increased levels of the other PGC-1 isoforms: PGC-1β and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1α via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1α downregulation. In contrast to the decrease in PGC-1α, estrogen increased protein levels of nuclear respiratory factor 1, a known PGC target and mediator of mitochondrial biogenesis. The latter effect of estrogen was independent of PI3K, suggesting a separate mechanism consistent with increased expression of PGC-1β and PRC. We demonstrated increased mitochondrial biogenesis following estrogen treatment in vivo; cerebrovascular levels of mitochondrial transcription factor A and electron transport chain subunits as well as the mitochondrial/nuclear DNA ratio were increased. We examined a downstream target of PGC-1β, glutamate-cysteine ligase (GCL), the rate-limiting enzyme for glutathione synthesis. In vivo estrogen increased protein levels of both GCL subunits and total glutathione levels. Together these data show estrogen differentially regulates PGC-1 isoforms in brain vasculature, underscoring the importance of these coactivators in adapting mitochondria in specific tissues. By upregulating PGC-1β and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection.
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Estrogen and progesterone contributed to sex differences in cellular respiration and anti-oxidative functions of brain mitochondria in uninjured female rodents.
“Estrogen and progesterone contributed to sex differences in cellular respiration and anti-oxidative functions of brain mitochondria in uninjured female rodents.”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [140]
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Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know
Gupte, R. P., Brooks, W. M., Vukas, R. R., Pierce, J. D., & Harris, J. L. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6171 · Cited by 533 · see citing works
- Authors
- Kemper, M. F., Stirone, C., Krause, D. N., Duckles, S. P., & Procaccio, V.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Krause, Diana N.
- ORCID
- Procaccio, Vincent
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 723
- Pages
- 322-329
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC4028038
- OpenAlex
- W2000288492
- Cited by
- 42
- References
- 44
- Citations by year
- 2026: 5 · 2025: 5 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 7 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01 HL-50775, R01HL050775)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- estrogen, estradiol, PGC-1α, PGC-1β, transcriptional coactivator, mitochondrial biogenesis, cerebral vasculature, reactive oxygen species, glutathione synthesis, gamma-glutamylcysteine synthetase, FOXO1, phosphatidylinositol 3-kinase, NRF1, mitochondrial DNA, ovariectomy
- MeSH terms
- Forkhead Box Protein O1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Triphosphate, Animals, Brain, Estradiol, Estrogens, Female, Glutamate-Cysteine Ligase, Glutathione, Mitochondria, Nerve Tissue Proteins, Ovariectomy, Rats, Inbred F344, RNA, Messenger, Transcription Factors, Reactive Oxygen Species, Protein Isoforms, Genomics, NF-E2-Related Factor 1, Rats, Forkhead Transcription Factors
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