AMPK-regulated miRNA-210-3p is activated during ischaemic neuronal injury and modulates PI3K-p70S6K signalling.

Autor: Pfeiffer S; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Tomašcová A; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Biomedical Centre Martin, Comenius University in Bratislava, Bratislava, Slovakia., Mamrak U; Institute for Stroke and Dementia Research (ISD), Munich, Germany., Haunsberger SJ; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Connolly NMC; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Resler A; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Düssmann H; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Weisová P; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Jirström E; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin, Ireland., D'Orsi B; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Institute of Neuroscience, Italian National Research Council (CNR), Pisa, Italy., Chen G; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Cremona M; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.; Dept of Molecular Medicine (Medical Oncology group), Royal College of Surgeons in Ireland, Dublin, Ireland., Hennessy BT; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.; Dept of Molecular Medicine (Medical Oncology group), Royal College of Surgeons in Ireland, Dublin, Ireland.; Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland., Plesnila N; Institute for Stroke and Dementia Research (ISD), Munich, Germany.; Munich Cluster of Systems Neurology (Synergy), Munich, Germany., Prehn JHM; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin, Ireland.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2021 Nov; Vol. 159 (4), pp. 710-728. Date of Electronic Publication: 2021 Mar 18.
DOI: 10.1111/jnc.15347
Abstrakt: 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.
(© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)
Databáze: MEDLINE
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