'Mild mitochondrial uncoupling' induced protection against neuronal excitotoxicity requires AMPK activity

Petronela Weisová, Ujval Anilkumar, Caitriona Ryan, Caoimhín G. Concannon, Jochen H.M. Prehn*, Manus W. Ward

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The preconditioning response conferred by a mild uncoupling of the mitochondrial membrane potential (Δψm) has been attributed to altered reactive oxygen species (ROS) production and mitochondrial Ca 2+ uptake within the cells. Here we have explored if altered cellular energetics in response to a mild mitochondrial uncoupling stimulus may also contribute to the protection. The addition of 100 nM FCCP for 30 min to cerebellar granule neurons (CGNs) induced a transient depolarization of the Δψm, that was sufficient to significantly reduce CGN vulnerability to the excitotoxic stimulus, glutamate. On investigation, the mild mitochondrial 'uncoupling' stimulus resulted in a significant increase in the plasma membrane levels of the glucose transporter isoform 3, with a hyperpolarisation of Δψm and increased cellular ATP levels also evident following the washout of FCCP. Furthermore, the phosphorylation state of AMP-activated protein kinase (AMPK) (Thr 172) was increased within 5 min of the uncoupling stimulus and elevated up to 1 h after washout. Significantly, the physiological changes and protection evident after the mild uncoupling stimulus were lost in CGNs when AMPK activity was inhibited. This study identifies an additional mechanism through which protection is mediated upon mild mitochondrial uncoupling: it implicates increased AMPK signalling and an adaptive shift in energy metabolism as mediators of the preconditioning response associated with FCCP-induced mild mitochondrial uncoupling.

Original languageEnglish (US)
Pages (from-to)744-753
Number of pages10
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1817
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by grants from the Royal College of Surgeons in Ireland (Research Committee grant 839 ) and the Health Research Board ( RP/2006/181 ) to M.W.W., Science Foundation Ireland ( 08/IN.1/B1949 ) to J.H.M.P., and the Higher Education Authority PRTLI Cycle 4 (National Biophotonics and Imaging Platform Ireland ). P.W. is supported by the VIPS Program (funded by Austrian Federal Ministry of Science and Research and City of Vienna).

Keywords

  • AMPK
  • ATP
  • Excitotoxicity
  • Mitochondrial bioenergetics
  • Neuronal preconditioning
  • Uncoupling

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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