Key Takeaways & Executive Findings
- •• linc-PMB is a novel mTOR-associated lncRNA that promotes mitochondrial biogenesis. • linc-PMB stabilizes SIRT1 mRNA by binding to HuR, increasing SIRT1 expression. • The SIRT1/PGC-1α/mtTFA axis is activated by linc-PMB, enhancing mitochondrial function. • This pathway offers potential therapeutic targets for mitochondrial dysfunction-related diseases.
Abstract
Mitochondrial dysfunction is implicated in numerous disorders, including type 2 diabetes, Alzheimer’s disease and cancer. Long non-coding RNAs (lncRNAs) are emerging as pivotal regulators of cellular energy metabolism, yet their roles remain largely unclear. In this study, we identify an lncRNA named linc-PMB, which is associated with mTOR and promotes mitochondrial biogenesis, through microarray analysis. We demonstrate that the knockdown of linc-PMB results in significantly impaired mitochondrial respiration and biogenesis, along with altered expressions of related genes. Conversely, overexpression of linc-PMB markedly increases mitochondrial function. We further reveal that linc-PMB interacts with the RNA-binding protein HuR, promoting the stabilization of SIRT1 mRNA and a substantial increase in SIRT1 expression, which in turn activates the PGC-1α/mtTFA pathway and mitochondrial biogenesis. Collectively, our findings reveal a novel regulatory pathway in which linc-PMB, through its interaction with HuR, modulates the SIRT1/PGC-1α/mtTFA axis to maintain mitochondrial biogenesis and function.
1. Introduction
Long non-coding RNAs (lncRNAs), defined as non-protein-coding transcripts longer than 200 nucleotides, constitute a significant portion of the mammalian transcriptome. They play regulatory roles in transcription through various mechanisms, including acting as signals, decoys, guides, and scaffolds, while also governing multiple aspects of post-transcriptional processes such as pre-mRNA processing and splicing, transport, translation, and degradation [1–3].
lncRNAs can extensively influence cellular functions by responding to various stimuli and interacting with key metabolic components and regulatory factors within signaling pathways [4]. Recent studies have revealed that lncRNAs engage in crosstalk with crucial signaling networks, such as Akt [5], WNT [6], Notch [7], and TGFβ [8], thereby modulating numerous cellular pathways and biological processes [2].
Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that consists of two distinct signaling complexes: mTORC1 and mTORC2. mTOR integrates signals from upstream pathways, including insulin, growth factors, amino acids, oxygen, and energy levels. Therefore, the mTOR pathway serves as a central coordinator of mammalian metabolism and physiology, playing key roles in the function of various tissues, including the liver, muscle, adipose tissue, and brain [9–11].
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Qian Chen, Huaying Zhang, Daokun Wang, Wenjing Liao, Yazhou Liu, Yurui Cai, Siyou Wang, Mengqian Yu (2026). mTOR-related linc-PMB promotes mitochondrial biogenesis via stabilizing SIRT1 mRNA through binding to the HuR protein. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024236
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Frequently Asked Questions
What is the role of linc-PMB in mitochondrial biogenesis?
linc-PMB promotes mitochondrial biogenesis by stabilizing SIRT1 mRNA through binding to HuR, leading to increased SIRT1 expression and activation of the PGC-1α/mtTFA pathway.
How does linc-PMB interact with HuR?
linc-PMB binds to the RNA-binding protein HuR, which stabilizes SIRT1 mRNA, preventing its degradation and enhancing SIRT1 protein levels.
What is the significance of the SIRT1/PGC-1α/mtTFA axis?
This axis is a key regulatory pathway for mitochondrial biogenesis and function. Activation of this axis by linc-PMB enhances mitochondrial respiration and biogenesis, which is crucial for cellular energy metabolism.
What are the potential therapeutic implications of this study?
The findings suggest that targeting linc-PMB or its interaction with HuR could be a novel therapeutic strategy for diseases associated with mitochondrial dysfunction, such as type 2 diabetes, Alzheimer's disease, and cancer.
How was linc-PMB identified?
linc-PMB was identified through microarray analysis of lncRNA expression changes in HepG2 cells treated with rapamycin, an mTOR inhibitor. It was selected for further study due to its significant expression change and potential role in mitochondrial biogenesis.
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