title: Targeted mitochondrial uncoupling beyond UCP1 - The fine line between death and metabolic health.
abstract: In the early 1930s, the chemical uncoupling agent 2,4-dinitrophenol (DNP) was promoted for the very first time as a powerful and effective weight loss pill but quickly withdrawn from the market due to its lack of tissue-selectivity with resulting dangerous side effects, including hyperthermia and death. Today, novel mitochondria- or tissue-targeted chemical uncouplers with higher safety and therapeutic values are under investigation in order to tackle obesity, diabetes and fatty liver disease. Moreover, in the past 20 years, transgenic mouse models were generated to understand the molecular and metabolic consequences of targeted uncoupling, expressing functional uncoupling protein 1 (UCP1) ectopically in white adipose tissue or skeletal muscle. Similar to the action of chemical mitochondrial uncouplers, UCP1 protein dissipates the proton gradient across the inner mitochondrial membrane, thus allowing maximum activity of the respiratory chain and compensatory increase in oxygen consumption, uncoupled from ATP synthesis. Consequently, targeted mitochondrial uncoupling in adipose tissue and skeletal muscle of UCP1-transgenic mice increased substrate metabolism and ameliorates obesity, hypertriglyceridemia and insulin resistance. Further, muscle-specific decrease in mitochondrial efficiency promotes a cell-autonomous and cell-non-autonomous adaptive metabolic remodeling with increased oxidative stress tolerance. This review provides an overview of novel chemical uncouplers as well as the metabolic consequences and adaptive processes of targeted mitochondrial uncoupling on metabolic health and survival.
authors.affiliation: Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Germany. Electronic address: Mario.ost@dife.de.
authors.forename: Mario
authors.initials: M
authors.lastname: Ost
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, 85764, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Keipert
authors.affiliation: Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klaus
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D019076:Transgenes; D014475:Uncoupling Agents / Q000494:pharmacology*; D000071256:Uncoupling Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D010971:Plastoquinone; D019297:2,4-Dinitrophenol
keywords: Energy metabolism; Longevity; Mitochondria; Obesity; Protonophore; Uncoupling protein 1