Cited by 42Mitochondrial Function and PathologyEstrogen and related hormone effectsAdipose Tissue and Metabolism

Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection

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Kemper, Martin F., Stirone, Chris, Krause, Diana N., Duckles, Sue P., Procaccio, Vincent·2014·European Journal of Pharmacology

Abstract

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.”

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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.
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2014-01
Volume
723
Pages
322-329
ISSN
0014-2999 (ISSN-L)
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
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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