TY - JOUR
T1 - Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice
AU - Lin, Ai Ling
AU - Pulliam, Daniel A.
AU - Deepa, Sathyaseelan S.
AU - Halloran, Jonathan J.
AU - Hussong, Stacy A.
AU - Burbank, Raquel R.
AU - Bresnen, Andrew
AU - Liu, Yuhong
AU - Podlutskaya, Natalia
AU - Soundararajan, Anuradha
AU - Muir, Eric
AU - Duong, Timothy Q.
AU - Bokov, Alex F.
AU - Viscomi, Carlo
AU - Zeviani, Massimo
AU - Richardson, Arlan G.
AU - Van Remmen, Holly
AU - Fox, Peter T.
AU - Galvan, Veronica
PY - 2013/10
Y1 - 2013/10
N2 - Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.
AB - Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.
KW - Surf1
KW - glucose metabolism
KW - memory
KW - mitochondrial complex IV
KW - mitochondrial dysfunction
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UR - http://www.scopus.com/inward/citedby.url?scp=84885020210&partnerID=8YFLogxK
U2 - 10.1038/jcbfm.2013.116
DO - 10.1038/jcbfm.2013.116
M3 - Article
C2 - 23838831
AN - SCOPUS:84885020210
SN - 0271-678X
VL - 33
SP - 1605
EP - 1611
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 10
ER -