The redox regulation of intermediary metabolism by a superoxide-aconitase rheostat.
In this article, we discuss a hypothesis to explain the preferential synthesis of the superoxide sensitive form of aconitase in mitochondria and the phenotype observed in manganese superoxide dismutase mutant mice, which show a gross over accumulation of stored fat in liver. The model proposes that intermediary metabolism is redox regulated by mitochondrial superoxide generated during mitochondrial respiration. This regulates the level of reducing equivalents (NADH) entering the electron transport chain (ETC) through the reversible inactivation of mitochondrial aconitase. This control mechanism has a dual function; firstly, it regulates levels of superoxide generated by the ETC and, secondly, it fine-tunes metabolism by channeling citrate either for the production of NADH for energy metabolism or diverting it for the synthesis of fats. In this setting, the mitochondrial redox state influences metabolic decisions via a superoxide-aconitase rheostat.
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Republic of Singapore. bchjsa@nus.edu.sg
Jeffrey S
JS
Armstrong
Matthew
M
Whiteman
Hongyuan
H
Yang
Dean P
DP
Jones
D000154:Aconitate Hydratase / Q000378:metabolism*; D000818:Animals; D019343:Citric Acid / Q000378:metabolism; D019143:Evolution, Molecular; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D016877:Oxidants; D017382:Reactive Oxygen Species; D013481:Superoxides; D019343:Citric Acid; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D000154:Aconitate Hydratase