AMPK-regulated miRNA-210-3p is activated during ischaemic neuronal injury and modulates PI3K-p70S6K signalling.
Shona PfeifferAnna TomašcováUta MamrakStefan J HaunsbergerNiamh M C ConnollyAlexa ReslerHeiko DüssmannPetronela WeisováElisabeth JirströmBeatrice D'OrsiGang ChenMattia CremonaBryan T HennessyNikolaus PlesnilaJochen H M PrehnPublished in: Journal of neurochemistry (2021)
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.
Keyphrases
- protein kinase
- binding protein
- skeletal muscle
- protein protein
- single cell
- spinal cord
- multiple sclerosis
- transcription factor
- cerebral ischemia
- amino acid
- intensive care unit
- high resolution
- stem cells
- high throughput
- poor prognosis
- liver failure
- drug induced
- cell proliferation
- cell therapy
- bone marrow
- diabetic rats
- acute respiratory distress syndrome
- subarachnoid hemorrhage
- single molecule
- long non coding rna
- endothelial cells
- heat stress
- mechanical ventilation