The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function
Open accessPublished version of a preprint
Abstract
PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that its RNA/NXF1-binding activity is required for the nuclear export of some canonical mitochondrial-related mRNAs and mitochondrial homeostasis. Genome-wide investigations reveal that the nuclear export function is not strictly linked to promoter-binding, identifying in turn novel regulatory targets of PGC-1α in non-homologous end-joining and nucleocytoplasmic transport. These findings provide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, aging and neurodegeneration.
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- Authors
- Mihaylov, S. R., Castelli, L. M., Lin, Y.-H., Gül, A., Soni, N., Hastings, C., Flynn, H. R., Păun, O., Dickman, M. J., Snijders, A. P., Goldstone, R., Bandmann, O., Shelkovnikova, T. A., Mortiboys, H., Ultanir, S. K., & Hautbergue, G. M.
- Affiliations
- The Francis Crick Institute (GB)
- University of Sheffield (GB)
- Corresponding author
- Hautbergue, Guillaume M.
- ORCID
- Venue
- Nature Communications
- Published
- 2023-09-07
- Volume
- 14
- Issue
- 1
- Pages
- 5496-5496
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10485026
- OpenAlex
- W4386508375
- Cited by
- 63
- References
- 7
- Citations by year
- 2026: 24 · 2025: 22 · 2024: 15 · 2023: 2
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Royal Society (RG140690)
- RCUK | Medical Research Council (MR/R024162/1)
- RCUK | Biotechnology and Biological Sciences Research Council (BB/S005277/1)
- Francis Crick Institute (FC001201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PGC-1α, nuclear export, NXF1, RNA recognition motif, mitochondrial homeostasis, energy metabolism, RNA binding, non-homologous end joining, nuclear transport, transcriptional coactivation, aging, neurodegeneration
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Homeostasis, Humans, RNA, Gene Expression, Active Transport, Cell Nucleus, RNA Transport
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