Abstract
The high-metabolic demand of neurons and their reliance on glucose as an energy source places them at risk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (Δψm) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased Δψm, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of Δψm to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochondrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 389-414 |
| Number of pages | 26 |
| Journal | NeuroMolecular Medicine |
| Volume | 8 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2006 |
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Keywords
- Caloric restriction
- Glucose transport
- Hippocampus
- Neuronal death
- Oxygen consumption
ASJC Scopus subject areas
- Neuroscience(all)
- Genetics
- Cell Biology
Cite this
Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. / Liu, Dong; Chan, Sic L.; De Souza-Pinto, Nadja C.; Slevin, John R.; Wersto, Robert P.; Zhan, Ming; Mustafa, Khadija; De Cabo, Rafael; Mattson, Mark P.
In: NeuroMolecular Medicine, Vol. 8, No. 3, 09.2006, p. 389-414.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress
AU - Liu, Dong
AU - Chan, Sic L.
AU - De Souza-Pinto, Nadja C.
AU - Slevin, John R.
AU - Wersto, Robert P.
AU - Zhan, Ming
AU - Mustafa, Khadija
AU - De Cabo, Rafael
AU - Mattson, Mark P.
PY - 2006/9
Y1 - 2006/9
N2 - The high-metabolic demand of neurons and their reliance on glucose as an energy source places them at risk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (Δψm) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased Δψm, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of Δψm to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochondrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload.
AB - The high-metabolic demand of neurons and their reliance on glucose as an energy source places them at risk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (Δψm) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased Δψm, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of Δψm to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochondrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload.
KW - Caloric restriction
KW - Glucose transport
KW - Hippocampus
KW - Neuronal death
KW - Oxygen consumption
UR - http://www.scopus.com/inward/record.url?scp=33745230018&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745230018&partnerID=8YFLogxK
U2 - 10.1385/NMM:8:3:389
DO - 10.1385/NMM:8:3:389
M3 - Article
C2 - 16775390
AN - SCOPUS:33745230018
VL - 8
SP - 389
EP - 414
JO - NeuroMolecular Medicine
JF - NeuroMolecular Medicine
SN - 1535-1084
IS - 3
ER -