Mitochondrial UCP4 Mediates an Adaptive Shift in Energy Metabolism and Increases the Resistance of Neurons to Metabolic and Oxidative Stress英文文献.pdfVIP

NeuroMolecular Medicine Copyright © 2006 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/06/08:389–414/$30.00 (Online) 1559-1174 doi: 10.1385/NMM:8:3:389 ORIGINAL ARTICLE Mitochondrial UCP4 Mediates an Adaptive Shift in Energy Metabolism and Increases the Resistance of Neurons to Metabolic and Oxidative Stress Dong Liu,†,1 Sic. L. Chan,†,1 Nadja C. de Souza-Pinto,2 John R. Slevin, Jr., 1 Robert P. Wersto,3 Ming Zhan,3 Khadija Mustafa,1 Rafael de Cabo,4 and Mark P. Mattson*,1,5 1Laboratory of Neurosciences; 2Laboratory of Molecular Gerontology; 3Research Resources Branch; 4Laboratory of Experimental Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD; 5Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD Received December 17, 2005; Revised February 21, 2006; Accepted February 23, 2006 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 reg- ulation of mitochondrial membrane potential (∆ψm) 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 ∆ψm, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accu- mulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sen- sitivity, and