NeuroMolecular Medicine

, Volume 8, Issue 3, pp 389–413 | Cite as

Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress

  • Dong Liu
  • Sic L. Chan
  • Nadja C. de Souza-Pinto
  • John R. SlevinJr.
  • Robert P. Wersto
  • Ming Zhan
  • Khadija Mustafa
  • Rafael de Cabo
  • Mark P. MattsonEmail author
Original Article


The high-metabolic demand of neurons and their reliance on glucose as an energy source places them atrisk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochodrial 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 mitochodnrial 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.


PC12 Cell Mitochondrial Membrane Potential Caloric Restriction Oligomycin NeuroMolecular Medicine Volume 
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© Humana Press Inc. 2006

Authors and Affiliations

  • Dong Liu
    • 1
  • Sic L. Chan
    • 1
  • Nadja C. de Souza-Pinto
    • 2
  • John R. SlevinJr.
    • 1
  • Robert P. Wersto
    • 3
  • Ming Zhan
    • 3
  • Khadija Mustafa
    • 1
  • Rafael de Cabo
    • 4
  • Mark P. Mattson
    • 1
    • 5
    Email author
  1. 1.Laboratory of NeurosciencesNational Institute on Aging Intramural Research ProgramBaltimore
  2. 2.Laboratory of Molecular GerontologyNational Institute of Aging Intramural Research ProgramBaltimore
  3. 3.Research Resources BranchNational Institute of Aging Intramural Research ProgramBaltimore
  4. 4.Laboratory of Experimental GerontologyNational Institute on Aging Intramural Research ProgramBaltimore
  5. 5.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimore

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