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 (Deltapsim) 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 Deltapsim, 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 Deltapsim 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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
authors.forename: Nadja C
authors.initials: NC
authors.lastname: de Souza-Pinto
authors.forename: John R
authors.initials: JR
authors.lastname: Slevin
authors.forename: Robert P
authors.initials: RP
authors.lastname: Wersto
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Khadija
authors.initials: K
authors.lastname: Mustafa
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D031204:Caloric Restriction; D002478:Cells, Cultured; D003080:Cold Temperature; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071245:Mitochondrial Uncoupling Proteins; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C494853:Slc25a27 protein, rat; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D010100:Oxygen; D002118:Calcium