TY - JOUR
T1 - 'Mild mitochondrial uncoupling' induced protection against neuronal excitotoxicity requires AMPK activity
AU - Weisová, Petronela
AU - Anilkumar, Ujval
AU - Ryan, Caitriona
AU - Concannon, Caoimhín G.
AU - Prehn, Jochen H.M.
AU - Ward, Manus
PY - 2012/5/1
Y1 - 2012/5/1
N2 -
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 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.
AB -
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 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.
KW - AMPK
KW - ATP
KW - Excitotoxicity
KW - Mitochondrial bioenergetics
KW - Neuronal preconditioning
KW - Uncoupling
UR - http://www.scopus.com/inward/record.url?scp=84858715059&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2012.01.016
DO - 10.1016/j.bbabio.2012.01.016
M3 - Article
C2 - 22336583
AN - SCOPUS:84858715059
SN - 0005-2728
VL - 1817
SP - 744
EP - 753
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
IS - 5
ER -