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. Slevin, Robert P. Wersto, Ming Zhan, Khadija Mustafa, Rafael De Cabo, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

157 Scopus citations


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 languageEnglish
Pages (from-to)389-413
Number of pages25
JournalNeuroMolecular Medicine
Issue number3
StatePublished - Sep 2006

Bibliographical note

Funding Information:
This research was supported by the intramural research program of the National institute on Ageing of the NIH. The authors thank G. Pan and K. Gabriel-son for providing UCP cDNAs, D. K. Ingram for providing brains from calorie restricted Fischer-344 rats, J. Stuart for help with the oxygen consumption assay, and E. Yavin and A. Cheng for providing oligodendrocyte and astrocyte cell cultures.


  • Caloric restriction
  • Glucose transport
  • Hippocampus
  • Neuronal death
  • Oxygen consumption

ASJC Scopus subject areas

  • Molecular Medicine
  • Neurology
  • Cellular and Molecular Neuroscience


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