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AMPK‐regulated miRNA‐210‐3p is activated during ischaemic neuronal injury and modulates PI3K‐p70S6K signalling
Author(s) -
Pfeiffer Shona,
Tomašcová Anna,
Mamrak Uta,
Haunsberger Stefan J.,
Connolly Niamh M. C.,
Resler Alexa,
Düssmann Heiko,
Weisová Petronela,
Jirström Elisabeth,
D’Orsi Beatrice,
Chen Gang,
Cremona Mattia,
Hennessy Bryan T.,
Plesnila Nikolaus,
Prehn Jochen H. M.
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15347
Subject(s) - ampk , ribosomal protein s6 , tensin , protein kinase a , mtorc1 , pi3k/akt/mtor pathway , ribosomal s6 kinase , microbiology and biotechnology , protein kinase b , amp activated protein kinase , kinase , chemistry , biology , signal transduction , pten , p70 s6 kinase 1
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.