'Mild mitochondrial uncoupling' induced protection against neuronal excitotoxicity requires AMPK activity.
Biochim Biophys Acta
; 1817(5): 744-53, 2012 May.
Article
in En
| MEDLINE
| ID: mdl-22336583
ABSTRACT
The preconditioning response conferred by a mild uncoupling of the mitochondrial membrane potential (Δψ(m)) 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 Δψ(m), 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 Δψ(m) 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 1h 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
/
Cytoprotection
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AMP-Activated Protein Kinases
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Mitochondria
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Neurons
/
Neurotoxins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Biochim Biophys Acta
Year:
2012
Document type:
Article
Affiliation country:
Ireland