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

Simeon R. Mihaylov, Lydia M. Castelli, Ya-Hui Lin, Aytac Gül, Nikita Soni, Christopher Hastings, Helen R. Flynn, Oana Păun, Mark J. Dickman, Ambrosius P. Snijders, Robert Goldstone, Oliver Bandmann, Tatyana A. Shelkovnikova, Heather Mortiboys, Sila K. Ultanir and Guillaume M. Hautbergue ()
Additional contact information
Simeon R. Mihaylov: University of Sheffield
Lydia M. Castelli: University of Sheffield
Ya-Hui Lin: University of Sheffield
Aytac Gül: University of Sheffield
Nikita Soni: University of Sheffield
Christopher Hastings: University of Sheffield
Helen R. Flynn: The Francis Crick Institute
Oana Păun: The Francis Crick Institute
Mark J. Dickman: University of Sheffield
Ambrosius P. Snijders: The Francis Crick Institute
Robert Goldstone: The Francis Crick Institute
Oliver Bandmann: University of Sheffield
Tatyana A. Shelkovnikova: University of Sheffield
Heather Mortiboys: University of Sheffield
Sila K. Ultanir: The Francis Crick Institute
Guillaume M. Hautbergue: University of Sheffield

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41304-8

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