title: Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit.
abstract: Cellular proteins rely on reversible redox reactions to establish and maintain biological structure and function. How redox catabolic (NAD+/NADH) and anabolic (NADP+/NADPH) processes integrate during metabolism to maintain cellular redox homoeostasis, however, is unknown. The present work identifies a continuously cycling mitochondrial membrane potential (ΔΨm)-dependent redox circuit between the pyruvate dehydrogenase complex (PDHC) and nicotinamide nucleotide transhydrogenase (NNT). PDHC is shown to produce H2O2 in relation to reducing pressure within the complex. The H2O2 produced, however, is effectively masked by a continuously cycling redox circuit that links, via glutathione/thioredoxin, to NNT, which catalyses the regeneration of NADPH from NADH at the expense of ΔΨm. The net effect is an automatic fine-tuning of NNT-mediated energy expenditure to metabolic balance at the level of PDHC. In mitochondria, genetic or pharmacological disruptions in the PDHC-NNT redox circuit negate counterbalance changes in energy expenditure. At the whole animal level, mice lacking functional NNT (C57BL/6J) are characterized by lower energy-expenditure rates, consistent with their well-known susceptibility to diet-induced obesity. These findings suggest the integration of redox sensing of metabolic balance with compensatory changes in energy expenditure provides a potential mechanism by which cellular redox homoeostasis is maintained and body weight is defended during periods of positive and negative energy balance.
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Kelsey H
authors: KH
authors: Fisher-Wellman
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Chien-Te
authors: CT
authors: Lin
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Terence E
authors: TE
authors: Ryan
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Lauren R
authors: LR
authors: Reese
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Laura A A
authors: LA
authors: Gilliam
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Brook L
authors: BL
authors: Cathey
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Daniel S
authors: DS
authors: Lark
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: Cody D
authors: CD
authors: Smith
authors: §Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, U.S.A.
authors: Deborah M
authors: DM
authors: Muoio
authors: *East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, U.S.A.
authors: P Darrell
authors: PD
authors: Neufer
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008931:Mitochondria, Muscle / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009249:NADP / Q000235:genetics / Q000378:metabolism*; D061087:NADP Transhydrogenase, AB-Specific / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D011768:Pyruvate Dehydrogenase Complex; D009249:NADP; D006861:Hydrogen Peroxide; D061087:NADP Transhydrogenase, AB-Specific; C556048:Nnt protein, mouse
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