The master energy homeostasis regulator PGC-1α couples transcriptional co-activation and mRNA nuclear export

Abstract

PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1α-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing and neurodegenerative diseases.

Robust, Precise, and Deep Proteome Profiling Using a Small Mass Range and Narrow Window Data-Independent-Acquisition Scheme

“…In contrast, mice lacking PGC-1α express higher levels of TNFα, supporting our findings. Moreover, the involvement of PGC-1α in mRNA processing has been demonstrated in vitro. − Our results confirm that proteins linked to this process are decreased in the absence of muscle PGC-1α. Therefore, this newly developed method contributes substantially to the detection of a higher number of proteins associated with various pathways and could thereby help identify novel target proteins.…”