Mitochondrial localization, import, and mitochondrial function of the androgen receptor
Open accessAbstract
Nuclear localization of androgen receptor (AR) directs transcriptional regulation of a host of genes, referred to as genomic signaling. Additionally, nonnuclear or nongenomic activities of the AR have long been described, but understanding of these activities remains elusive. Here, we report that AR is imported into and localizes to mitochondria and has a novel role in regulating multiple mitochondrial processes. Employing complementary experimental approaches of AR knockdown in AR-expressing cells and ectopic AR expression in AR-deficient cells, we demonstrate an inverse relationship between AR expression and mitochondrial DNA (mtDNA) content and transcription factor A, mitochondrial (TFAM), a regulator of mtDNA content. We show that AR localizes to mitochondria in prostate tissues and cell lines and is imported into mitochondria in vitro . We also found that AR contains a 36-amino-acid-long mitochondrial localization sequence (MLS) capable of targeting a passenger protein (GFP) to the mitochondria and that deletion of the MLS abolishes the import of AR into the mitochondria. Ectopic AR expression reduced the expression of oxidative phosphorylation (OXPHOS) subunits. Interestingly, AR also controlled translation of mtDNA-encoded genes by regulating expression of multiple nuclear DNA-encoded mitochondrial ribosomal proteins. Consistent with these observations, OXPHOS supercomplexes were destabilized, and OXPHOS enzymatic activities were reduced in AR-expressing cells and restored upon AR knockdown. Moreover, mitochondrial impairment induced AR expression and increased its translocation into mitochondria. We conclude that AR localizes to mitochondria, where it controls multiple mitochondrial functions and mitonuclear communication. Our studies also suggest that mitochondria are novel players in nongenomic activities of AR.
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AR localizes into mitochondria.
“Notably, Similar to the Localization of estrogen receptors (ERα and ERβ), a recent study has shown that besides being nuclear, AR also localizes into mitochondria (150).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [150]
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From mitochondria to sarcopenia: role of 17β-estradiol and testosterone
Tian, X., Lou, S., & Shi, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1156583 · Cited by 54 · see citing works
- Authors
- Bajpai, P., Koc, E., Sonpavde, G., Singh, R., & Singh, K. K.
- Affiliations
- University of Alabama at Birmingham (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Singh, Keshav K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 294
- Issue
- 16
- Pages
- 6621-6634
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6484137
- OpenAlex
- W2917942389
- Cited by
- 99
- References
- 71
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 17 · 2023: 23 · 2022: 13 · 2021: 14 · 2020: 11 · 2019: 3
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R01 CA204430)
- Indo-US Science and Technology Forum (2016/120)
- Mike Slive Foundation for Prostate Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- androgen receptor, mitochondrial localization, mitochondrial protein import, mitochondrial DNA content, TFAM, oxidative phosphorylation, mitochondrial ribosomal proteins, prostate
- MeSH terms
- PC-3 Cells, DNA-Binding Proteins, Humans, Mitochondria, Oxidative Phosphorylation, Receptors, Androgen, Transcription Factors, Protein Transport, Protein Sorting Signals, Mitochondrial Proteins, Gene Knockdown Techniques
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