Endogenous Ovarian Hormones Affect Mitochondrial Efficiency in Cerebral Endothelium via Distinct Regulation of PGC-1 Isoforms
Open accessAbstract
Mitochondria support the energy-intensive functions of brain endothelium but also produce damaging-free radicals that lead to disease. Previously, we found that estrogen treatment protects cerebrovascular mitochondria, increasing capacity for ATP production while decreasing reactive oxygen species (ROS). To determine whether these effects occur specifically in endothelium in vivo and also explore underlying transcriptional mechanisms, we studied freshly isolated brain endothelial preparations from intact and ovariectomized female mice. This preparation reflects physiologic influences of circulating hormones, hemodynamic forces, and cell–cell interactions of the neurovascular unit. Loss of ovarian hormones affected endothelial expression of the key mitochondrial regulator family, peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), but in a unique way. Ovariectomy increased endothelial PGC-1α mRNA but decreased PGC-1β mRNA. The change in PGC-1β correlated with decreased mRNA for crucial downstream mitochondrial regulators, nuclear respiratory factor 1 and mitochondrial transcription factor A, as well as for ATP synthase and ROS protection enzymes, glutamate-cysteine ligase and manganese superoxide dismutase. Ovariectomy also decreased mitochondrial biogenesis (mitochondrial/nuclear DNA ratio). These results indicate ovarian hormones normally act through a distinctive regulatory pathway involving PGC-1β to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS 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 [139]
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- Authors
- Kemper, M. F., Zhao, Y., Duckles, S. P., & Krause, D. N.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Krause, Diana N
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2012-10-24
- Volume
- 33
- Issue
- 1
- Pages
- 122-128
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC3597365
- OpenAlex
- W1993575616
- Cited by
- 38
- References
- 41
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 3
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (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
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- ovarian hormones, estrogen, PGC-1α, PGC-1β, brain endothelium, mitochondrial biogenesis, reactive oxygen species, ATP production, ovariectomy, neurovascular unit, mitochondrial DNA, manganese superoxide dismutase, gamma-glutamylcysteine synthetase, NRF1, TFAM, ATP synthase
- MeSH terms
- Animals, Cerebral Cortex, DNA, Mitochondrial, Endothelium, Vascular, Estrogens, Female, Mice, Inbred C57BL, Mitochondria, Muscle, Ovariectomy, Ovary, Transcription Factors, Blotting, Western, Down-Regulation, Up-Regulation, Reactive Oxygen Species, Mitochondrial Proton-Translocating ATPases, Estrogen Receptor alpha, Estrogen Receptor beta, Mice, Nitric Oxide Synthase Type III, Real-Time Polymerase Chain Reaction
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