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AMPK-regulated miRNA-210-3p is activated during ischaemic neuronal injury and modulates P13K-p70S6K signalling

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Progressive neuronal injury following ischaemic stroke is associated with glutamate-induced depolarization, energetic stress and activation of AMP-activated protein kinase (AMPK). We here identify a molecular signature associated with neuronal AMPK activation, as a critical regulator of cellular response to energetic stress following ischaemia. We report a robust induction of microRNA miR-210-3p both in vitro in primary cortical neurons in response to acute AMPK activation and following ischaemic stroke in vivo. Bioinformatics and reverse phase protein array analysis of neuronal protein expression changes in vivo following administration of a miR-210-3p mimic revealed altered expression of phosphatase and tensin homolog (PTEN), 3-phosphoinositide-dependent protein kinase 1 (PDK1), ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (RPS6) signalling in response to increasing miR-210-3p. In vivo, we observed a corresponding reduction in p70S6K activity following ischaemic stroke. Utilizing models of glutamate receptor over-activation in primary neurons, we demonstrated that induction of miR-210-3p was accompanied by sustained suppression of p70S6K activity and that this effect was reversed by miR-210-3p inhibition. Collectively, these results provide new molecular insight into the regulation of cell signalling during ischaemic injury, and suggest a novel mechanism whereby AMPK regulates miR-210-3p to control p70S6K activity in ischaemic stroke and excitotoxic injury.

Funding

Munich Cluster of Systems Neurology (SyNergy; Project ID EXC2145/ID390857198)

RCSI International StAR Ph.D. studentship

SFI (13/IA/1881; 17/COEN/3474)

History

Comments

The original article is available at https://onlinelibrary.wiley.com/

Published Citation

Pfeiffer S. et al. AMPK-regulated miRNA-210-3p is activated during ischaemic neuronal injury and modulates PI3K-p70S6K signalling. J Neurochem. 2021;159(4):710-728

Publication Date

11 March 2021

PubMed ID

33694332

Department/Unit

  • Beaumont Hospital
  • Centre for Systems Medicine
  • FutureNeuro Centre
  • Molecular Medicine
  • Physiology and Medical Physics

Research Area

  • Neurological and Psychiatric Disorders
  • Cancer

Publisher

Wiley

Version

  • Published Version (Version of Record)