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 journalArticle

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 languageEnglish (US)
Pages (from-to)389-414
Number of pages26
JournalNeuroMolecular Medicine
Volume8
Issue number3
DOIs
StatePublished - Sep 2006

Fingerprint

Physiological Stress
Energy Metabolism
Oxidative Stress
Neurons
Reactive Oxygen Species
Caloric Restriction
Calcium
Brain
Respiration
Adenosine Triphosphate
Oligomycins
Glucose
Messenger RNA
Mitochondrial Membrane Potential
Neuroprotective Agents
Glycolysis
RNA Interference
Oxygen Consumption
Membrane Proteins
Cell Death

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 journalArticle

Liu, D, Chan, SL, De Souza-Pinto, NC, Slevin, JR, Wersto, RP, Zhan, M, Mustafa, K, De Cabo, R & Mattson, MP 2006, 'Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress', NeuroMolecular Medicine, vol. 8, no. 3, pp. 389-414. https://doi.org/10.1385/NMM:8:3:389
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. / Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. In: NeuroMolecular Medicine. 2006 ; Vol. 8, No. 3. pp. 389-414.
@article{002e348486f1467e8d8066a229199710,
title = "Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress",
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.",
keywords = "Caloric restriction, Glucose transport, Hippocampus, Neuronal death, Oxygen consumption",
author = "Dong Liu and Chan, {Sic L.} and {De Souza-Pinto}, {Nadja C.} and Slevin, {John R.} and Wersto, {Robert P.} and Ming Zhan and Khadija Mustafa and {De Cabo}, Rafael and Mattson, {Mark P.}",
year = "2006",
month = "9",
doi = "10.1385/NMM:8:3:389",
language = "English (US)",
volume = "8",
pages = "389--414",
journal = "NeuroMolecular Medicine",
issn = "1535-1084",
publisher = "Humana Press",
number = "3",

}

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 -