Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die

Jee Yeon Hwang, Michael Gertner, Fabrizio Pontarelli, Brenda Court-Vazquez, Michael V. L. Bennett, Dimitry Ofengeim, R. Suzanne Zukin

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy. This is significant in that autophagy, a catabolic process downstream of mTORC1, promotes the formation of autophagosomes that capture and target cytoplasmic components to lysosomes. Inhibitors of the lysosomal (but not proteasomal) pathway rescued the ischemia-induced decrease in mTOR, consistent with degradation of mTOR via the autophagy/lysosomal pathway. Administration of the mTORC1 inhibitor rapamycin or acute knockdown of mTOR promotes autophagy and attenuates ischemia-induced neuronal death, indicating an inverse causal relation between mTOR, autophagy, and neuronal death. Our findings identify a novel and previously unappreciated mechanism by which mTOR self-regulates its own levels in hippocampal neurons in a clinically relevant model of ischemic stroke.

Original languageEnglish (US)
Pages (from-to)317-329
Number of pages13
JournalCell Death and Differentiation
Volume24
Issue number2
DOIs
StatePublished - Feb 1 2017

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Autophagy
Sirolimus
Ischemia
Neurons
Autistic Disorder
Lysosomes
Biomarkers
Stroke
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. / Hwang, Jee Yeon; Gertner, Michael; Pontarelli, Fabrizio; Court-Vazquez, Brenda; Bennett, Michael V. L.; Ofengeim, Dimitry; Zukin, R. Suzanne.

In: Cell Death and Differentiation, Vol. 24, No. 2, 01.02.2017, p. 317-329.

Research output: Contribution to journalArticle

Hwang, Jee Yeon ; Gertner, Michael ; Pontarelli, Fabrizio ; Court-Vazquez, Brenda ; Bennett, Michael V. L. ; Ofengeim, Dimitry ; Zukin, R. Suzanne. / Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 2. pp. 317-329.
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