The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function

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.

Metadata

Item Type:	Article
Authors/Creators:	Mihaylov, S.R. https://orcid.org/0000-0001-6872-0635 Castelli, L.M. Lin, Y.-H. https://orcid.org/0000-0003-1576-4655 Gül, A. https://orcid.org/0000-0002-0578-8058 Soni, N. https://orcid.org/0000-0001-5120-1695 Hastings, C. Flynn, H.R. https://orcid.org/0000-0001-7002-9130 Păun, O. Dickman, M.J. https://orcid.org/0000-0002-9236-0788 Snijders, A.P. Goldstone, R. Bandmann, O. https://orcid.org/0000-0003-3149-0252 Shelkovnikova, T.A. Mortiboys, H. https://orcid.org/0000-0001-6439-0579 Ultanir, S.K. https://orcid.org/0000-0001-5745-3957 Hautbergue, G.M. https://orcid.org/0000-0002-1621-261X
Copyright, Publisher and Additional Information:	© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	RNA; RNA transport
Dates:	Published: 7 September 2023 Published (online): 7 September 2023 Accepted: 30 August 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	14 Sep 2023 08:35
Last Modified:	14 Sep 2023 08:35
Published Version:	http://dx.doi.org/10.1038/s41467-023-41304-8
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-023-41304-8
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:203266

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The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function

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