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Alpha-lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice
Hiller, S., R. DeKroon, L. Xu, J. Robinette, W. Winnik, O. Alzate, S. Simington, N. Maeda, AND X. Yi. Alpha-lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice. Free Radical Biology and Medicine. Elsevier Science Ltd, New York, NY, 71:362-7, (2014).
Abstract: Hypothermia is a key symptom of sepsis and the mechanism(s) leading to hypothermia during sepsis is largely unknown. To investigate a potential mechanism and find an effective treatment for hypothermia in sepsis, we induced hypothermia in mice by lipopolysaccharide (LPS) injection. Our results show that treatment with α-lipoic acid (LA) effectively attenuates LPS-induced hypothermia with decreased nitric oxide production in wild type mice whereas iNOS-null mice did not suffer obvious hypothermia. In addition, LA treatment resumed ATP production decreased in septic mice and ameliorated the oxygen consumption rate reduced by excessive nitric oxide as observed in in vitro experiments. These data strongly suggest that hypothermia during sepsis is related to mitochondrial dysfunction likely compromised by excessive nitric oxide production. Using proteomic analysis, we identified nitrosylated subunits of complex III and α-ketoglutarate dehydrogenase complex. S-nitrosylation of these subunits consequently decreased activities of these enzymes while LA supplementation decreased S-nitrosylation, partially restoring enzymatic activities. We conclude that LA-dependent thermoregulation is mainly mediated through protection of mitochondrial function and regulation of protein S-nitrosylation during sepsis.
This manuscript resulted from collaboration with UNC. Most of the laboratory work was performed at UNC and the burden on EPA-NHEERL resources was marginal. From the perspective of the NHEERL RCU Proteomics Core, the project was aimed at developing a new method for detection and quantitation of S-nitrosylated proteins: biomarkers of oxidative stress and of certain diseases. The new methodology is expected to benefit the EPA projects, performed in collaboration with the RCU Proteomics Research Core, which are in need of oxidative stress assessment.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
ASSOCIATE DIRECTOR FOR HEALTH
RESEARCH CORES UNIT