Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases

Mitchell, 1967, Chemiosmotic Hypothesis of Oxidative Phosphorylation, Nature, 213, 137, 10.1038/213137a0

Jonckheere, 2012, Mitochondrial ATP synthase: Architecture, function and pathology, J. Inherit. Metab. Dis., 35, 211, 10.1007/s10545-011-9382-9

Jastroch, 2010, Mitochondrial proton and electron leaks, Essays Biochem., 47, 53, 10.1042/bse0470053

Kadenbach, 2003, Intrinsic and extrinsic uncoupling of oxidative phosphorylation, Biochim. Biophys. Acta, 1604, 77, 10.1016/S0005-2728(03)00027-6

Murphy, 1989, Slip and leak in mitochondrial oxidative phosphorylation, Biochim. Biophys. Acta, 977, 123, 10.1016/S0005-2728(89)80063-5

Gnaiger, E., Aasander Frostner, E., Abdul Karim, N., Abdel-Rahman, E.A., Abumrad, N.A., Acuna-Castroviejo, D., Adiele, R.C., Ahn, B., Alencar, M.B., and Ali, S.S. (2019). Mitochondrial respiratory states and rates. MitoFit Preprint Arch.

Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression, J. Biol. Chem., 260, 16250, 10.1016/S0021-9258(17)36228-2

Rial, 1983, Brown-adipose-tissue mitochondria: The regulation of the 32000-Mr uncoupling protein by fatty acids and purine nucleotides, JBIC J. Biol. Inorg. Chem., 137, 197

Strieleman, 1985, Fatty acid activation of the reconstituted brown adipose tissue mitochondria uncoupling protein, J. Biol. Chem., 260, 13402, 10.1016/S0021-9258(17)38735-5

Carroll, 2008, Identification of serine phosphorylation in mitochondrial uncoupling protein 1, Biochim. Biophys. Acta, 1777, 1060, 10.1016/j.bbabio.2008.04.030

Crichton, 2017, The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism, Biochimie, 134, 35, 10.1016/j.biochi.2016.12.016

Nedergaard, 2001, UCP1: The only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency, Biochim. Biophys. Acta, 1504, 82, 10.1016/S0005-2728(00)00247-4

Bouillaud, 2009, UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing, Biochim. Biophys. Acta, 1787, 377, 10.1016/j.bbabio.2009.01.003

Shabalina, 2011, Mitochondrial (‘mild’) uncoupling and ROS production: Physiologically relevant or not?, Biochem. Soc. Trans., 39, 1305, 10.1042/BST0391305

Stuart, 2001, Physiological Levels of Mammalian Uncoupling Protein 2 Do Not Uncouple Yeast Mitochondria, J. Biol. Chem., 276, 18633, 10.1074/jbc.M011566200

Rial, 1999, Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2, EMBO J., 18, 5827, 10.1093/emboj/18.21.5827

Couplan, 2002, No Evidence for a Basal, Retinoic, or Superoxide-induced Uncoupling Activity of the Uncoupling Protein 2 Present in Spleen or Lung Mitochondria, J. Biol. Chem., 277, 26268, 10.1074/jbc.M202535200

Berardi, 2014, Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria, Cell Metab., 20, 541, 10.1016/j.cmet.2014.07.004

Mozo, 2006, Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose, Biochem. J., 393, 431, 10.1042/BJ20050494

Cadenas, 1999, UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged, FEBS Lett., 462, 257, 10.1016/S0014-5793(99)01540-9

Harper, 2002, Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria, Biochem. J., 361, 49, 10.1042/bj3610049

Busiello, 2015, Mitochondrial uncoupling proteins and energy metabolism, Front. Physiol., 6, 36, 10.3389/fphys.2015.00036

Andreyev, 1989, The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria, JBIC J. Biol. Inorg. Chem., 182, 585

Sparks, 2016, ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity, Diabetologia, 59, 1030, 10.1007/s00125-016-3885-8

Brand, 2005, The basal proton conductance of mitochondria depends on adenine nucleotide translocase content, Biochem. J., 392, 353, 10.1042/BJ20050890

Bouillaud, 2016, UCPs, at the interface between bioenergetics and metabolism, Biochim. Biophys. Acta, 1863, 2443, 10.1016/j.bbamcr.2016.04.013

Brenner, 2011, Adenine nucleotide translocase family: Four isoforms for apoptosis modulation in cancer, Oncogene, 30, 883, 10.1038/onc.2010.501

Bukowiecki, 1981, Metabolic relationships between lipolysis and respiration in rat brown adipocytes. The role of long chain fatty acids as regulators of mitochondrial respiration and feedback inhibitors of lipolysis, J. Biol. Chem., 256, 12840, 10.1016/S0021-9258(18)42972-9

Wojtczak, 1993, Effect of fatty acids on energy coupling processes in mitochondria, Biochim. Biophys. Acta, 1183, 41, 10.1016/0005-2728(93)90004-Y

Bernardi, 2002, Mitochondrial energy dissipation by fatty acids. Mechanisms and implications for cell death, TRAIL, 65, 97

Garlid, 2018, Mitochondrial uncoupling proteins: Subtle regulators of cellular redox signaling, Antioxid. Redox Signal., 29, 667

Divakaruni, 2012, Fatty Acids Change the Conformation of Uncoupling Protein 1 (UCP1), J. Biol. Chem., 287, 36845, 10.1074/jbc.M112.381780

Matthias, 1999, The bioenergetics of brown fat mitochondria from UCP1-ablated mice. Ucp1 is not involved in fatty acid-induced de-energization (“uncoupling”), J. Biol. Chem., 274, 28150, 10.1074/jbc.274.40.28150

Monemdjou, 1999, Mitochondrial proton leak in brown adipose tissue mitochondria of Ucp1-deficient mice is GDP insensitive, Am. J. Physiol. Metab., 276, 1073

Hofmann, 2001, Effects of Genetic Background on Thermoregulation and Fatty Acid-induced Uncoupling of Mitochondria in UCP1-deficient Mice, J. Biol. Chem., 276, 12460, 10.1074/jbc.M100466200

Shabalina, 2016, Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria, Arch. Toxicol., 90, 1117, 10.1007/s00204-015-1535-4

Villarroya, 2017, Transcriptional regulation of the uncoupling protein-1 gene, Biochimie, 134, 86, 10.1016/j.biochi.2016.09.017

Xu, 2018, Cold exposure induces nuclear translocation of CRTC3 in brown adipose tissue, J. Cell. Biochem., 120, 9138, 10.1002/jcb.28189

Cao, 2004, p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene, Mol. Cell. Biol., 24, 3057, 10.1128/MCB.24.7.3057-3067.2004

Rehnmark, 1990, Alpha- and beta-adrenergic induction of the expression of the uncoupling protein thermogenin in brown adipocytes differentiated in culture, J. Biol. Chem., 265, 16464, 10.1016/S0021-9258(17)46245-4

Champigny, 1992, Regulation of UCP gene expression in brown adipocytes differentiated in primary culture. Effects of a new beta-adrenoceptor agonist, Mol. Cell. Endocrinol., 86, 73, 10.1016/0303-7207(92)90177-8

Silva, 1988, Full Expression of Uncoupling Protein Gene Requires the Concurrence of Norepinephrine and Triiodothyronine, Mol. Endocrinol., 2, 706, 10.1210/mend-2-8-706

Herron, 1990, Norepinephrine-induced synthesis of the uncoupling protein thermogenin (UCP) and its mitochondrial targeting in brown adipocytes differentiated in culture, FEBS Lett., 268, 296, 10.1016/0014-5793(90)81031-I

Champigny, 1996, Evidence from in vitro differentiating cells that adrenoceptor agonists can increase uncoupling protein mRNA level in adipocytes of adult humans: An RT-PCR study, J. Lipid Res., 37, 1907, 10.1016/S0022-2275(20)37555-6

Kenwood, 2014, Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane, Mol. Metab., 3, 114, 10.1016/j.molmet.2013.11.005

Wang, 2018, Uncoupling effect of F16 is responsible for its mitochondrial toxicity and anticancer activity, Toxicol. Sci., 161, 431, 10.1093/toxsci/kfx218

Figarola, 2012, Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis, Investig. New Drugs, 30, 1413, 10.1007/s10637-011-9711-8

Sztark, 1997, Effects of the local anesthetic bupivacaine on mitochondrial energy metabolism: Change from uncoupling to decoupling depending on the respiration state, IUBMB Life, 43, 997, 10.1080/15216549700204811

Severin, 2010, Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore, Proc. Natl. Acad. Sci. USA, 107, 663, 10.1073/pnas.0910216107

Benz, 1983, The molecular mechanism of action of the proton ionophore FCCP (carbonylcyanide p-trifluoromethoxyphenylhydrazone), Biophys. J., 41, 381, 10.1016/S0006-3495(83)84449-X

Kasianowicz, 1984, The kinetic mechanism by which CCCP (carbonyl cyanide m-chlorophenylhydrazone) transports protons across membranes, J. Membr. Biol., 82, 179, 10.1007/BF01868942

Kaczara, 2015, Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: A role for mitoBKCa channels, Biochim. Biophys. Acta, 1847, 1297, 10.1016/j.bbabio.2015.07.004

Loomis, 1948, Reversible inhibition of the coupling between phosphorylation and oxidation, J. Biol. Chem., 173, 807, 10.1016/S0021-9258(18)57455-X

Urra, 2018, FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway, Sci. Rep., 8, 13190, 10.1038/s41598-018-31367-9

Hanley, 1998, Mechanisms of force inhibition by halothane and isoflurane in intact rat cardiac muscle, J. Physiol., 506, 231, 10.1111/j.1469-7793.1998.231bx.x

Schiffer, T.A., Christensen, M., Gustafsson, H., and Palm, F. (2018). The effect of inactin on kidney mitochondrial function and production of reactive oxygen species. PLoS ONE, 13.

Denisov, 2014, A mitochondria-targeted protonophoric uncoupler derived from fluorescein, Chem. Commun., 50, 15366, 10.1039/C4CC04996A

Chalmers, 2012, Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore, J. Am. Chem. Soc., 134, 758, 10.1021/ja2077922

Lin, 2018, Discovery of hydrolysis-resistant isoindoline N-acyl amino acid analogs that stimulate mitochondrial respiration, J. Med. Chem., 61, 3224, 10.1021/acs.jmedchem.8b00029

Khailova, 2014, A short-chain alkyl derivative of Rhodamine 19 acts as a mild uncoupler of mitochondria and a neuroprotector, Biochim. Biophys. Acta, 1837, 1739, 10.1016/j.bbabio.2014.07.006

Yau, 2019, Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy, Autophagy, 15, 131, 10.1080/15548627.2018.1511263

Masuda, 2003, Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog, J. Appl. Physiol., 95, 2408, 10.1152/japplphysiol.00828.2002

Kida, 2016, Direct action of capsaicin in brown adipogenesis and activation of brown adipocytes, Cell Biochem. Funct., 34, 34, 10.1002/cbf.3162

Saito, 2015, Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis, Adv. Food Nutr. Res., 76, 1, 10.1016/bs.afnr.2015.07.002

Kida, 2018, Supra-pharmacological concentration of capsaicin stimulates brown adipogenesis through induction of endoplasmic reticulum stress, Sci. Rep., 8, 845, 10.1038/s41598-018-19223-2

Jancso, 1985, Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat, Neurosci. Lett., 59, 209, 10.1016/0304-3940(85)90201-0

Bargut, T.C.L., Martins, F.F., Santos, L.P., Aguila, M.B., and Mandarim-de-Lacerda, C.A. (2018). Administration of eicosapentaenoic and docosahexaenoic acids may improve the remodeling and browning in subcutaneous white adipose tissue and thermogenic markers in brown adipose tissue in mice. Mol. Cell. Endocrinol.

Zhao, 2014, Eicosapentaenoic acid promotes thermogenic and fatty acid storage capacity in mouse subcutaneous adipocytes, Biochem. Biophys. Res. Commun., 450, 1446, 10.1016/j.bbrc.2014.07.010

Oudart, 1997, Brown fat thermogenesis in rats fed high-fat diets enriched with n-3 polyunsaturated fatty acids, Int. J. Obes., 21, 955, 10.1038/sj.ijo.0800500

Takahashi, 2000, Dietary n-3 fatty acids affect mRNA level of brown adipose tissue uncoupling protein 1, and white adipose tissue leptin and glucose transporter 4 in the rat, Br. J. Nutr., 84, 175, 10.1017/S0007114500001409

Laiglesia, 2016, Eicosapentaenoic acid promotes mitochondrial biogenesis and beige-like features in subcutaneous adipocytes from overweight subjects, J. Nutr. Biochem., 37, 76, 10.1016/j.jnutbio.2016.07.019

Silva, 1997, Regulation of the uncoupling protein gene expression, Eur. J. Endocrinol., 136, 251, 10.1530/eje.0.1360251

Kleszczyński, K., Bilska, B., Stegemann, A., Flis, D.J., Ziolkowski, W., Pyza, E., Luger, T.A., Reiter, R.J., Böhm, M., and Slominski, A.T. (2018). Melatonin and Its Metabolites Ameliorate UVR-Induced Mitochondrial Oxidative Stress in Human MNT-1 Melanoma Cells. Int. J. Mol. Sci., 19.

Hollenbeck, 1985, Effects of the uncoupling agents FCCP and CCCP on the saltatory movements of cytoplasmic organelles, Cell Biol. Int. Rep., 9, 193, 10.1016/0309-1651(85)90094-3

Park, 2002, FCCP depolarizes plasma membrane potential by activating proton and Na+ currents in bovine aortic endothelial cells, Pflug. Arch., 443, 344, 10.1007/s004240100703

Juthberg, 1997, Effect of Metabolic Inhibitors on Membrane Potential and Ion Conductance of Rat Astrocytes, Cell. Mol. Neurobiol., 17, 367, 10.1023/A:1026331226241

Duchen, 1990, Effects of metabolic inhibition on the membrane properties of isolated mouse primary sensory neurones, J. Physiol., 424, 387, 10.1113/jphysiol.1990.sp018073

Brismar, 1993, Effect of external cation concentration and metabolic inhibitors on membrane potential of human glial cells, J. Physiol., 460, 365, 10.1113/jphysiol.1993.sp019476

Antonenko, 2016, A long-linker conjugate of fluorescein and triphenylphosphonium as mitochondria-targeted uncoupler and fluorescent neuro- and nephroprotector, Biochim. Biophys. Acta, 1860, 2463, 10.1016/j.bbagen.2016.07.014

Rottenberg, 1983, Uncoupling of oxidative phosphorylation in rat liver mitochondria by general anesthetics, Proc. Natl. Acad. Sci. USA, 80, 3313, 10.1073/pnas.80.11.3313

Pravdic, 2012, Complex I and ATP synthase mediate membrane depolarization and matrix acidification by isoflurane in mitochondria, Eur. J. Pharmacol., 690, 149, 10.1016/j.ejphar.2012.07.003

Rokitskaya, 2016, Weak C–H acids as protonophores can carry hydrogen ions through lipid membranes and mitochondria: A case of o-carborane, Phys. Chem. Chem. Phys., 18, 16476, 10.1039/C6CP02581A

Padman, 2013, The protonophore CCCP interferes with lysosomal degradation of autophagic cargo in yeast and mammalian cells, Autophagy, 9, 1862, 10.4161/auto.26557

Johnson, 2016, The position of lysosomes within the cell determines their luminal pH, J. Cell Biol., 212, 677, 10.1083/jcb.201507112

Narendra, 2008, Parkin is recruited selectively to impaired mitochondria and promotes their autophagy, J. Cell Biol., 183, 795, 10.1083/jcb.200809125

Feng, 2014, The machinery of macroautophagy, Cell Res., 24, 24, 10.1038/cr.2013.168

Cuervo, 2014, Chaperone-mediated autophagy: Roles in disease and aging, Cell Res., 24, 92, 10.1038/cr.2013.153

Li, 2012, Microautophagy: Lesser-known self-eating, Cell. Mol. Life Sci., 69, 1125, 10.1007/s00018-011-0865-5

Galluzzi, 2017, Molecular definitions of autophagy and related processes, EMBO J., 36, 1811, 10.15252/embj.201796697

Lyamzaev, 2018, Induction of autophagy by depolarization of mitochondria, Autophagy, 14, 921, 10.1080/15548627.2018.1436937

Demine, 2018, Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes, J. Cell. Physiol., 233, 1247, 10.1002/jcp.25994

Kwon, 2011, CCCP induces autophagy in an AMPK-independent manner, Biochem. Biophys. Res. Commun., 416, 343, 10.1016/j.bbrc.2011.11.038

Chan, 2011, Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy, Hum. Mol. Genet., 20, 1726, 10.1093/hmg/ddr048

Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem., 134, 677, 10.1111/jnc.13176

Romaschenko, 2015, Low concentrations of uncouplers of oxidative phosphorylation prevent inflammatory activation of endothelial cells by tumor necrosis factor, Biochemistry, 80, 610

Si, 2007, Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism, J. Lipid Res., 48, 826, 10.1194/jlr.M600343-JLR200

Sachdev, 2018, Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis, Biochim. Biophys. Acta Mol. Cell. Biol. Lipids, 1863, 467

Liu, 2016, FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes, Cell Death Discov., 2, 16066, 10.1038/cddiscovery.2016.66

Zhang, 2016, The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy, Am. J. Physiol. Heart Circ. Physiol., 310, H29, 10.1152/ajpheart.00926.2014

Radad, 2015, Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture, Folia Neuropathol., 3, 250, 10.5114/fn.2015.54426

Itami, 2015, Mitochondrial biogenesis and degradation are induced by CCCP treatment of porcine oocytes, Reproduction, 150, 97, 10.1530/REP-15-0037

Callegari, 2017, Phospho-ubiquitin-PARK2 complex as a marker for mitophagy defects, Autophagy, 13, 201, 10.1080/15548627.2016.1254852

Lee, 2010, Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy, J. Cell Biol., 189, 671, 10.1083/jcb.201001039

Ding, 2010, Nix Is Critical to Two Distinct Phases of Mitophagy, Reactive Oxygen Species-mediated Autophagy Induction and Parkin-Ubiquitin-p62-mediated Mitochondrial Priming, J. Biol. Chem., 285, 27879, 10.1074/jbc.M110.119537

Harris, 2018, Mitophagy and the release of inflammatory cytokines, Mitochondrion, 41, 2, 10.1016/j.mito.2017.10.009

Pickles, 2018, Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance, Curr. Biol., 28, R170, 10.1016/j.cub.2018.01.004

Zhang, 2010, Reticulocyte mitophagy: Monitoring mitochondrial clearance in a mammalian model, Autophagy, 6, 405, 10.4161/auto.6.3.11245

Brady, 2007, Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy, Cell Death Differ., 14, 146, 10.1038/sj.cdd.4401936

Lu, 2018, Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge, Sci. Rep., 8, 8251, 10.1038/s41598-018-26394-5

Wang, 2017, Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells, Oncotarget, 8, 70406, 10.18632/oncotarget.19710

Song, 2016, Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization, Proc. Natl. Acad. Sci. USA, 113, E5261, 10.1073/pnas.1605844113

Shin, 2019, Inhibition of bioenergetics provides novel insights into recruitment of PINK 1-dependent neuronal mitophagy, J. Neurochem., 149, 269, 10.1111/jnc.14667

Chu, 2013, Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells, Nature, 15, 1197

Berezhnov, 2016, Intracellular pH Modulates Autophagy and Mitophagy, J. Biol. Chem., 291, 8701, 10.1074/jbc.M115.691774

Yin, 2013, The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation, Autophagy, 9, 1687, 10.4161/auto.24871

Liang, 2014, PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism, Cell Metab., 19, 836, 10.1016/j.cmet.2014.03.023

Li, 2018, PTENα regulates mitophagy and maintains mitochondrial quality control, Autophagy, 14, 1, 10.1080/15548627.2018.1444314

Bento, 2018, UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy, Sci. Rep., 8, 12415, 10.1038/s41598-018-30963-z

Xiao, 2017, Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria, Cell Death Dis., 8, e3097, 10.1038/cddis.2017.463

Rakovic, 2018, PINK1-dependent mitophagy is driven by the UPS and can occur independently of LC3 conversion, Cell Death Differ., 26, 1428, 10.1038/s41418-018-0219-z

Cheng, 2016, MicroRNA-181a suppresses parkin-mediated mitophagy and sensitizes neuroblastoma cells to mitochondrial uncoupler-induced apoptosis, Oncotarget, 7, 42274, 10.18632/oncotarget.9786

Kubli, D.A., Cortez, M.Q., Moyzis, A.G., Najor, R.H., Lee, Y., and Gustafsson, Å.B. (2015). PINK1 Is Dispensable for Mitochondrial Recruitment of Parkin and Activation of Mitophagy in Cardiac Myocytes. PLoS ONE, 10.

Lombard, 2011, Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation, Handb. Exp. Pharmacol., 206, 163, 10.1007/978-3-642-21631-2_8

Singh, 2018, The Role of Sirtuins in Antioxidant and Redox Signaling, Antioxid. Redox Signal., 28, 643, 10.1089/ars.2017.7290

Li, 2018, SIRT4 is the last puzzle of mitochondrial sirtuins, Bioorg. Med. Chem., 26, 3861, 10.1016/j.bmc.2018.07.031

Lang, 2017, SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy, Aging, 9, 2163, 10.18632/aging.101307

MacVicar, 2014, Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation, J. Cell Sci., 127, 2313

Chen, 2016, Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy, Autophagy, 12, 689, 10.1080/15548627.2016.1151580

Ma, 2016, Peroxiredoxin 6 Is a Crucial Factor in the Initial Step of Mitochondrial Clearance and Is Upstream of the PINK1-Parkin Pathway, Antioxid. Redox Signal., 24, 486, 10.1089/ars.2015.6336

Bartolomé, A., García-Aguilar, A., Asahara, S.-I., Kido, Y., Guillén, C., Pajvani, U.B., and Benito, M. (2017). MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling. Mol. Cell. Biol.

Hirota, 2015, Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways, Autophagy, 11, 332, 10.1080/15548627.2015.1023047

Ivankovic, 2016, Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy, J. Neurochem., 136, 388, 10.1111/jnc.13412

Itoh, 2015, Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria, J. Clin. Biochem. Nutr., 56, 91, 10.3164/jcbn.14-134

Ghislat, 2016, Transcriptional regulation of mammalian autophagy at a glance, J. Cell Sci., 129, 3059, 10.1242/jcs.188920

Blessing, 2017, Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression, Autophagy, 13, 506, 10.1080/15548627.2016.1268300

Park, 2015, p62 prevents carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell death by activating Nrf2, Biochem. Biophys. Res. Commun., 464, 1139, 10.1016/j.bbrc.2015.07.093

Tahara, 2009, Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation, Free. Radic. Biol. Med., 46, 1283, 10.1016/j.freeradbiomed.2009.02.008

Lambert, 2004, Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane, Biochem. J., 382, 511, 10.1042/BJ20040485

Kushnareva, 2002, Complex I-mediated reactive oxygen species generation: Modulation by cytochrome c and NAD(P)+ oxidation-reduction state, Biochem. J., 368, 545, 10.1042/bj20021121

Barja, 2007, Mitochondrial Oxygen Consumption and Reactive Oxygen Species Production are Independently Modulated: Implications for Aging Studies, Rejuvenation Res., 10, 215, 10.1089/rej.2006.0516

Turrens, 1982, Hyperoxia increases H2O2 release by lung mitochondria and microsomes, Arch. Biochem. Biophys., 217, 411, 10.1016/0003-9861(82)90519-7

Hoffman, 2007, Response of mitochondrial reactive oxygen species generation to steady-state oxygen tension: Implications for hypoxic cell signaling, Am. J. Physiol. Circ. Physiol., 292, 101, 10.1152/ajpheart.00699.2006

Boveris, 1973, The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen, Biochem. J., 134, 707, 10.1042/bj1340707

Shabalina, 2014, ROS production in brown adipose tissue mitochondria: The question of UCP1-dependence, Biochim. Biophys. Acta, 1837, 2017, 10.1016/j.bbabio.2014.04.005

Zhang, 2016, Mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone induces vasorelaxation without involving K ATP channel activation in smooth muscle cells of arteries, Br. J. Pharmacol., 173, 3145, 10.1111/bph.13578

Li, 1999, Detection of mitochondria-derived reactive oxygen species production by the chemilumigenic probes lucigenin and luminol, Biochim. Biophys. Acta, 1428, 1, 10.1016/S0304-4165(99)00040-9

Oelkrug, 2010, Uncoupling Protein 1 Decreases Superoxide Production in Brown Adipose Tissue Mitochondria, J. Biol. Chem., 285, 21961, 10.1074/jbc.M110.122861

Stier, 2014, Mitochondrial uncoupling prevents cold-induced oxidative stress: A case study using UCP1 knockout mice, J. Exp. Biol., 217, 624

Clarke, 2010, The role of UCP 1 in production of reactive oxygen species by mitochondria isolated from brown adipose tissue, Biochim. Biophys. Acta, 1797, 1470, 10.1016/j.bbabio.2010.04.008

Kazak, 2017, UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction, Proc. Natl. Acad. Sci. USA, 114, 7981, 10.1073/pnas.1705406114

Wojtczak, 2012, Brown adipose tissue mitochondria oxidizing fatty acids generate high levels of reactive oxygen species irrespective of the uncoupling protein-1 activity state, Biochim. Biophys. Acta, 1817, 410, 10.1016/j.bbabio.2011.12.009

Chouchani, 2016, Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1, Nature, 532, 112, 10.1038/nature17399

Cadenas, 2018, Mitochondrial uncoupling, ROS generation and cardioprotection, Biochim. Biophys. Acta Bioenerg., 1859, 940, 10.1016/j.bbabio.2018.05.019

MacLellan, 2005, Physiological Increases in Uncoupling Protein 3 Augment Fatty Acid Oxidation and Decrease Reactive Oxygen Species Production Without Uncoupling Respiration in Muscle Cells, Diabetes, 54, 2343, 10.2337/diabetes.54.8.2343

Jun, 2015, UCP2 protects against amyloid beta toxicity and oxidative stress in primary neuronal culture, Biomed. Pharmacother., 74, 211, 10.1016/j.biopha.2015.08.001

Morrow, 2017, Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity, Proc. Natl. Acad. Sci. USA, 114, 2705, 10.1073/pnas.1700997114

Zhang, 2017, Transcription factor NF-kappa B represses ANT1 transcription and leads to mitochondrial dysfunctions, Sci. Rep., 7, 44708, 10.1038/srep44708

Ma, 2015, Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells, Bioorg. Med. Chem. Lett., 25, 4828, 10.1016/j.bmcl.2015.06.073

Antoine, 1986, Multiple effects of the phenylhydrazone derivative FCCP on the secretory pathway in rat plasma cells, Eur. J. Cell Biol., 42, 68

Argon, 1989, Two steps in the intracellular transport of IgD are sensitive to energy depletion, J. Immunol., 142, 554, 10.4049/jimmunol.142.2.554

Connop, 1999, Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing, J. Neurochem., 72, 1457, 10.1046/j.1471-4159.1999.721457.x

Giorgi, 2018, The machineries, regulation and cellular functions of mitochondrial calcium, Nat. Rev. Mol. Cell Biol., 19, 713, 10.1038/s41580-018-0052-8

Rottenberg, 1974, Calcium uptake and membrane potential in mitochondria, Biochemistry, 13, 4811, 10.1021/bi00720a020

Giovannucci, 1999, Mitochondria regulate the Ca(2+)-exocytosis relationship of bovine adrenal chromaffin cells, J. Neurosci., 19, 9261, 10.1523/JNEUROSCI.19-21-09261.1999

Jurkiewicz, 2013, Novel features on the regulation by mitochondria of calcium and secretion transients in chromaffin cells challenged with acetylcholine at 37°C, Physiol. Rep., 1, e00182, 10.1002/phy2.182

Jurkiewicz, 2009, Role of the Endoplasmic Reticulum and Mitochondria on Quantal Catecholamine Release from Chromaffin Cells of Control and Hypertensive Rats, J. Pharmacol. Exp. Ther., 329, 231, 10.1124/jpet.108.147413

Fuentealba, 2005, Depolarization evokes different patterns of calcium signals and exocytosis in bovine and mouse chromaffin cells: The role of mitochondria, Eur. J. Neurosci., 21, 142, 10.1111/j.1460-9568.2004.03861.x

Jhun, B.S., Lee, H., Jin, Z.-G., and Yoon, Y. (2013). Glucose Stimulation Induces Dynamic Change of Mitochondrial Morphology to Promote Insulin Secretion in the Insulinoma Cell Line INS-1E. PLoS ONE, 8.

Leloup, 2009, Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion, Diabetes, 58, 673, 10.2337/db07-1056

Barg, 2001, Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification, J. Cell Sci., 114, 2145, 10.1242/jcs.114.11.2145

Sharoyko, 2014, Chronic high glucose and pyruvate levels differentially affect mitochondrial bioenergetics and fuel-stimulated insulin secretion from clonal INS-1 832/13 cells, J. Biol. Chem., 289, 3786, 10.1074/jbc.M113.507335

Winn, 2017, Loss of UCP1 exacerbates Western diet-induced glycemic dysregulation independent of changes in body weight in female mice, Am. J. Physiol. Regul. Integr. Comp. Physiol., 312, R74, 10.1152/ajpregu.00425.2016

Nakazaki, 2002, Association of upregulated activity of K(ATP) channels with impaired insulin secretion in UCP1-expressing insulinoma cells, J. Physiol., 540, 781, 10.1113/jphysiol.2001.013048

Keipert, 2014, Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine, Am. J. Physiol. Metab., 306, 469

Mayoral, 2018, Mitohormesis, an Antiaging Paradigm, Int. Rev. Cell Mol. Biol., 340, 35, 10.1016/bs.ircmb.2018.05.002

Brennan, 2006, FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation, Cardiovasc. Res., 72, 322, 10.1016/j.cardiores.2006.08.006

Brennan, 2006, Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation, Cardiovasc. Res., 72, 313, 10.1016/j.cardiores.2006.07.019

Derdak, 2008, The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells, Cancer Res., 68, 2813, 10.1158/0008-5472.CAN-08-0053

Pozza, 2012, Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine, Biochim. Biophys. Acta, 1823, 1856, 10.1016/j.bbamcr.2012.06.007

Yu, 2015, Uncoupling protein 2 mediates resistance to gemcitabine-induced apoptosis in hepatocellular carcinoma cell lines, Biosci. Rep., 35, e00231, 10.1042/BSR20150116

Samaiya, 2018, 2,4 Dinitrophenol Attenuates Mitochondrial Dysfunction and Improves Neurobehavioral Outcomes Postanoxia in Neonatal Rats, Neurotox. Res., 34, 121, 10.1007/s12640-018-9873-7

Liu, 2017, Mitochondrial protein UCP1 mediates liver injury induced by LPS through EKR signaling pathway, Eur. Rev. Med. Pharmacol. Sci., 21, 3674

Adams, 2010, Absence of mitochondrial uncoupling protein 1 affects apoptosis in thymocytes, thymocyte/T-cell profile and peripheral T-cell number, Biochim. Biophys. Acta, 1797, 807, 10.1016/j.bbabio.2010.04.016

Zamora, 2004, Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis, J. Biol. Chem., 279, 38415, 10.1074/jbc.M404928200

Bauer, 1999, Adenine Nucleotide Translocase-1, a Component of the Permeability Transition Pore, Can Dominantly Induce Apoptosis, J. Cell Biol., 147, 1493, 10.1083/jcb.147.7.1493

Baines, 2009, Adenine nucleotide translocase-1 induces cardiomyocyte death through upregulation of the pro-apoptotic protein bax, J. Mol. Cell. Cardiol., 46, 969, 10.1016/j.yjmcc.2009.01.016

Machida, 2002, A Novel Adenine Nucleotide Translocase Inhibitor, MT-21, Induces CytochromecRelease by a Mitochondrial Permeability Transition-independent Mechanism, J. Biol. Chem., 277, 31243, 10.1074/jbc.M204564200

Nilsson, M.I., and Tarnopolsky, M.A. (2019). Mitochondria and Aging—The Role of Exercise as a Countermeasure. Biology, 8.

Ko, 2018, Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts, Pflug. Arch., 470, 263, 10.1007/s00424-017-2076-x

Zoladz, 2016, Endurance training increases the efficiency of rat skeletal muscle mitochondria, Pflug. Arch. Eur. J. Physiol., 468, 1709, 10.1007/s00424-016-1867-9

Crane, J.D., Abadi, A., Hettinga, B.P., Ogborn, D.I., MacNeil, L.G., Steinberg, G.R., and Tarnopolsky, M.A. (2013). Elevated Mitochondrial Oxidative Stress Impairs Metabolic Adaptations to Exercise in Skeletal Muscle. PLoS ONE, 8.

Phielix, 2010, Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals, Diabetologia, 53, 1714, 10.1007/s00125-010-1764-2

Kenny, 2017, Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance, Diabetologia, 60, 1491, 10.1007/s00125-017-4298-z

Gaspar, 2019, Acute physical exercise increases leptin-induced hypothalamic extracellular signal-regulated kinase1/2 phosphorylation and thermogenesis of obese mice, J. Cell. Biochem., 120, 697, 10.1002/jcb.27426

Kim, 2018, Effect of acute mid-intensity treadmill exercise on the androgen hormone level and uncoupling protein-1 expression in brown fat tissue of mouse, J. Exerc. Nutr. Biochem., 22, 15, 10.20463/jenb.2018.0003

Shirkhani, 2018, Comparative studies on the effects of high-fat diet, endurance training and obesity on Ucp1 expression in male C57BL/6 mice, Gene, 676, 16, 10.1016/j.gene.2018.07.015

Wauman, 2018, The intracellular domain of the leptin receptor prevents mitochondrial depolarization and mitophagy, Biochim. Biophys. Acta Mol. Cell. Res., 1865, 1312, 10.1016/j.bbamcr.2018.06.009

Silva, 2016, Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: The reversal effects of physical exercise, Aging, 9, 142, 10.18632/aging.101138

Portari, 2017, Effects of intermittent fasting and chronic swimming exercise on body composition and lipid metabolism, Appl. Physiol. Nutr. Metab., 42, 1341, 10.1139/apnm-2017-0435

Heras, 2018, Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue, Front. Physiol., 9, 1122, 10.3389/fphys.2018.01122

Knuth, 2018, Prior exercise training improves cold tolerance independent of indices associated with non-shivering thermogenesis, J. Physiol., 596, 4375, 10.1113/JP276228

Maarbjerg, 2011, AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise, Proc. Natl. Acad. Sci. USA, 108, 16092, 10.1073/pnas.1105062108

Leal, 2018, Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases, Front. Physiol., 9, 1307, 10.3389/fphys.2018.01307

Roca-Rivada, A., Castelao, C., Senin, L.L., Landrove, M.O., Baltar, J., Crujeiras, A.B., Seoane, L.M., Casanueva, F.F., and Pardo, M. (2013). FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine. PLoS ONE, 8.

2018, Irisin a Novel Metabolic biomarker: Present knowledge and future directions, Int. J. Endocrinol., 2018, 7816806

Wu, 2012, A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis, Nature, 481, 463, 10.1038/nature10777

Xin, 2016, Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway, Int. J. Obes., 40, 443, 10.1038/ijo.2015.199

Kazeminasab, 2018, A comparative study on the effects of high-fat diet and endurance training on the PGC-1α-FNDC5/irisin pathway in obese and nonobese male C57BL/6 mice, Appl. Physiol. Nutr. Metab., 43, 651, 10.1139/apnm-2017-0614

Zhang, 2017, Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism, Bone Res., 5, 16056, 10.1038/boneres.2016.56

Tekin, 2018, Central irisin administration suppresses thyroid hormone production but increases energy consumption in rats, Neurosci. Lett., 674, 136, 10.1016/j.neulet.2018.03.046

Zhang, 2016, Irisin exerts dual effects on browning and adipogenesis of human white adipocytes, Am. J. Physiol. Metab., 311, E530

Barquissau, 2018, Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity, Cell Rep., 22, 1079, 10.1016/j.celrep.2017.12.102

Schlagowski, 2014, Mitochondrial uncoupling reduces exercise capacity despite several skeletal muscle metabolic adaptations, J. Appl. Physiol., 116, 364, 10.1152/japplphysiol.01177.2013

Byrne, 1989, Prolonged aerobic exercise: Physiological studies in rat gastrocnemius with additional observations on the effects of acute mitochondrial blockade, J. Neurol. Sci., 92, 215, 10.1016/0022-510X(89)90138-X

Marit, 2011, Acute exposure to 2,4-dinitrophenol alters zebrafish swimming performance and whole body triglyceride levels, Comp. Biochem. Physiol. Part C Toxicol. Pharmacol., 154, 14, 10.1016/j.cbpc.2011.03.001

Couplan, 2002, High Level of Uncoupling Protein 1 Expression in Muscle of Transgenic Mice Selectively Affects Muscles at Rest and Decreases Their IIb Fiber Content, J. Biol. Chem., 277, 43079, 10.1074/jbc.M206726200

Voigt, 2015, Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity, Genes Nutr., 10, 57, 10.1007/s12263-015-0507-x

Rutkowski, 2015, The cell biology of fat expansion, J. Cell Biol., 208, 501, 10.1083/jcb.201409063

Schulz, 2013, Brown adipose tissue: Development, metabolism and beyond, Biochem. J., 453, 167, 10.1042/BJ20130457

Harms, 2013, Brown and beige fat: Development, function and therapeutic potential, Nat. Med., 19, 1252, 10.1038/nm.3361

Cao, 2014, Adipocytokines in Obesity and Metabolic Disease, J. Endocrinol., 220, T47, 10.1530/JOE-13-0339

Kaisanlahti, 2018, Browning of white fat: Agents and implications for beige adipose tissue to type 2 diabetes, J. Physiol. Biochem., 75, 1, 10.1007/s13105-018-0658-5

Jani, 2019, Cold acclimation enhances UCP1 content, lipolysis, and triacylglycerol resynthesis, but not mitochondrial uncoupling and fat oxidation, in rat white adipocytes, Am. J. Physiol. Physiol., 316, C365, 10.1152/ajpcell.00122.2018

Shinoda, 2016, Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance, Cell Metab., 24, 402, 10.1016/j.cmet.2016.08.002

Lu, 2018, Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism, Sci. Signal., 11, eaap8526, 10.1126/scisignal.aap8526

Taylor, 2017, Parkin-mediated mitophagy is downregulated in browning of white adipose tissue, Obesity, 25, 704, 10.1002/oby.21786

Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med., 2, 388, 10.1002/emmm.201000097

Budanov, 2004, Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD, Science, 304, 596, 10.1126/science.1095569

Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation, 41, 626, 10.1007/s10753-017-0718-y

Costa, 2018, Mitochondrial dysfunction in obesity, Life Sci., 192, 26, 10.1016/j.lfs.2017.11.019

Engin, 2017, What is lipotoxicity?, Adv. Exp. Med. Biol., 960, 197, 10.1007/978-3-319-48382-5_8

Marseglia, 2014, Oxidative Stress in Obesity: A Critical Component in Human Diseases, Int. J. Mol. Sci., 16, 378, 10.3390/ijms16010378

Aroor, 2014, Oxidative Stress and Obesity: The Chicken or the Egg?, Diabetes, 63, 2216, 10.2337/db14-0424

Bautista, 2011, Inflammation, Oxidative Stress, and Obesity, Int. J. Mol. Sci., 12, 3117, 10.3390/ijms12053117

Schmidt, F.M., Weschenfelder, J., Sander, C., Minkwitz, J., Thormann, J., Chittka, T., Mergl, R., Kirkby, K.C., Faßhauer, M., and Stumvoll, M. (2015). Inflammatory Cytokines in General and Central Obesity and Modulating Effects of Physical Activity. PLoS ONE, 10.

Kang, Y.E., Kim, J.M., Joung, K.H., Lee, J.H., You, B.R., Choi, M.J., Ryu, M.J., Ko, Y.B., Lee, M.A., and Lee, J. (2016). The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction. PLoS ONE, 11.

Ahmad, 2017, Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity, Immun. Inflamm. Dis., 5, 318, 10.1002/iid3.170

Skurk, 2005, The proatherogenic cytokine interleukin-18 is secreted by human adipocytes, Eur. J. Endocrinol., 152, 863, 10.1530/eje.1.01897

Seljeflot, 2010, The role of interleukin-18 in the metabolic syndrome, Cardiovasc. Diabetol., 9, 11, 10.1186/1475-2840-9-11

Yamanishi, 2018, Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia, J. Transl. Med., 16, 314, 10.1186/s12967-018-1684-3

Pazos, 2015, Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice, Sci. Rep., 5, 17977, 10.1038/srep17977

Veress, 2019, Interleukin-6 released from differentiating human beige adipocytes improves browning, Exp. Cell Res., 377, 47, 10.1016/j.yexcr.2019.02.015

Castaner, 2018, The Gut Microbiome Profile in Obesity: A Systematic Review, Int. J. Endocrinol., 2018, 1, 10.1155/2018/9109451

Cani, 2018, Gut microbiota-mediated inflammation in obesity: A link with gastrointestinal cancer, Nat. Rev. Gastroenterol. Hepatol., 15, 671, 10.1038/s41575-018-0025-6

Rastelli, 2018, Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders, Obesity, 26, 792, 10.1002/oby.22175

Fabbiano, 2015, Microbiota depletion promotes browning of white adipose tissue and reduces obesity, Nat. Med., 21, 1497, 10.1038/nm.3994

Moreno-Navarrete, J.M., Serino, M., Blasco-Baque, V., Azalbert, V., Barton, R.H., Cardellini, M., Latorre, J., Ortega, F., Sabater-Masdeu, M., and Burcelin, R. (2018). Gut microbiota interacts with markers of adipose tissue browning, insulin action and plasma acetate in morbid obesity. Mol. Nutr. Food Res., 62.

Li, 2017, Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota, Cell Metab., 26, 672, 10.1016/j.cmet.2017.08.019

Fabbiano, 2018, Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements, Cell Metab., 28, 907, 10.1016/j.cmet.2018.08.005

Chevalier, 2015, Gut Microbiota Orchestrates Energy Homeostasis during Cold, Cell, 163, 1360, 10.1016/j.cell.2015.11.004

Matejkova, 2004, Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat, FEBS Lett., 569, 245, 10.1016/j.febslet.2004.06.002

Neschen, 2008, Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo, Physiol. Genom., 33, 333, 10.1152/physiolgenomics.00226.2007

Han, 2004, UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction, Am. J. Physiol. Metab., 286, 347

Figarola, 2015, SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells, J. Biol. Chem., 290, 30321, 10.1074/jbc.M115.686352

Singhal, 2012, 1,3-bis(3,5-dichlorophenyl) Urea Compound ‘COH-SR4’ Inhibits Proliferation and Activates Apoptosis in Melanoma, Biochem. Pharmacol., 84, 1419, 10.1016/j.bcp.2012.08.020

Singhal, 2013, Novel Compound 1, 3-bis (3, 5-dichlorophenyl) urea Inhibits Lung Cancer Progression, Biochem. Pharmacol., 86, 1664, 10.1016/j.bcp.2013.09.022

Anilkumar, 2012, ‘Mild mitochondrial uncoupling’ induced protection against neuronal excitotoxicity requires AMPK activity, Biochim. Biophys. Acta, 1817, 744, 10.1016/j.bbabio.2012.01.016

Klaus, 2012, Augmenting energy expenditure by mitochondrial uncoupling: A role of AMP-activated protein kinase, Genes Nutr., 7, 369, 10.1007/s12263-011-0260-8

Ost, M., Werner, F., Dokas, J., Klaus, S., and Voigt, A. (2014). Activation of AMPKα2 Is Not Crucial for Mitochondrial Uncoupling-Induced Metabolic Effects but Required to Maintain Skeletal Muscle Integrity. PLoS ONE, 9.

Ingbe, S.Z., and Carlson-Lynch, H. (1995). Toxicological Profile for Dinitrophenols.

Margo, 2014, Diet pills and the cataract outbreak of 1935: Reflections on the evolution of consumer protection legislation, Surv. Ophthalmol., 59, 568, 10.1016/j.survophthal.2014.02.005

Horner, 1936, Cataract following di-nitrophenol treatment for obesity, Arch. Ophthalmol., 16, 447, 10.1001/archopht.1936.00840210121009

Izumoto, 2017, Sensory axonal polyneuropathy due to 2,4-dinitrophenol, Rinsho Shinkeigaku, 57, 599, 10.5692/clinicalneurol.cn-001062

Kamour, 2015, Increasing frequency of severe clinical toxicity after use of 2,4-dinitrophenol in the UK: A report from the National Poisons Information Service, Emerg. Med. J., 32, 383, 10.1136/emermed-2013-203335

Grundlingh, 2011, 2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death, J. Med. Toxicol., 7, 205, 10.1007/s13181-011-0162-6

Lee, 2014, 2,4-Dinitrophenol: A threat to Chinese body-conscious groups, J. Chin. Med. Assoc., 77, 443, 10.1016/j.jcma.2014.05.003

Holborow, A., Purnell, R.M., and Wong, J.F. (2016). Beware the yellow slimming pill: Fatal 2,4-dinitrophenol overdose. BMJ Case Rep., 2016.

Geisler, J.G. (2019). 2,4 Dinitrophenol as Medicine. Cells, 8.

Goldgof, 2014, The Chemical Uncoupler 2,4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality, J. Biol. Chem., 289, 19341, 10.1074/jbc.M114.568204

Michael, 2017, Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neurons to promote weight-loss, Mol. Metab., 6, 1103, 10.1016/j.molmet.2017.07.002

Lee, 2017, Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion, Int. J. Obes., 41, 645, 10.1038/ijo.2017.3

Takahashi, 2012, Induction of mitochondrial uncoupling enhances VEGF₁₂₀ but reduces MCP-1 release in mature 3T3-L1 adipocytes: Possible regulatory mechanism through endogenous ER stress and AMPK-related pathways, Biochem. Biophys. Res. Commun., 419, 200, 10.1016/j.bbrc.2012.01.145

Tejerina, 2009, Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARgamma-independent mechanism, whereas TNFalpha-induced de-differentiation is PPARgamma dependent, J. Cell Sci., 122, 145, 10.1242/jcs.027508

Demine, 2012, Mild mitochondrial uncoupling does not affect mitochondrial biogenesis but downregulates pyruvate carboxylase in adipocytes: Role for triglyceride content reduction, Am. J. Physiol. Metab., 302, E1123

Rossmeisl, 2005, Triglyceride-lowering Effect of Respiratory Uncoupling in White Adipose Tissue, Obes. Res., 13, 835, 10.1038/oby.2005.96

Ouchi, 2011, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol., 11, 85, 10.1038/nri2921

Perry, 2015, Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats, Science, 347, 1253, 10.1126/science.aaa0672

Abulizi, 2017, A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice, FASEB J., 31, 2916, 10.1096/fj.201700001R

Wei, 2017, Sustained-release mitochondrial protonophore reverses nonalcoholic fatty liver disease in rats, Int. J. Pharm., 530, 230, 10.1016/j.ijpharm.2017.07.072

Fakhri, 2014, The effect of salsalate on biochemical factors and endothelial dysfunction of prediabetic patients: A randomized clinical trial, J. Res. Med. Sci., 19, 287

Smith, 2016, Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1, Diabetes, 65, 3352, 10.2337/db16-0564

Worsch, 2018, Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice, Nutr. Metab., 15, 65, 10.1186/s12986-018-0291-x

Skulachev, 1991, Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation, FEBS Lett., 294, 158, 10.1016/0014-5793(91)80658-P

Fisher, 2012, FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis, Genes Dev., 26, 271, 10.1101/gad.177857.111

Dossi, 2014, Reversal of high-fat diet-induced hepatic steatosis by n-3 LCPUFA: Role of PPAR-α and SREBP-1c, J. Nutr. Biochem., 25, 977, 10.1016/j.jnutbio.2014.04.011

Flachs, 2005, Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat, Diabetologia, 48, 2365, 10.1007/s00125-005-1944-7

Van Schothorst, E.M., Flachs, P., Hal, N.L.F.-V., Kuda, O., Bunschoten, A., Molthoff, J., Vink, C., Hooiveld, G.J.E.J., Kopecky, J., and Keijer, J. (2009). Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet. BMC Genom., 10.

Montesanto, 2018, Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: Further evidence of association in Frontotemporal dementia, Aging, 10, 3283, 10.18632/aging.101632

Montesanto, 2016, The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer’s Disease and Modifies the Disease’s Risk in APOE-ɛ4 Carriers, J. Alzheimers Dis., 51, 1265, 10.3233/JAD-150993

Wu, 2013, Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels, Neuron, 78, 57, 10.1016/j.neuron.2013.02.028

Montaner, 2017, The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke after Recanalization, NeuroMol. Med., 19, 571, 10.1007/s12017-017-8470-x

Normoyle, 2015, The emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury, Transl. Neurosci., 6, 179, 10.1515/tnsci-2015-0019

Hass, 2016, Uncoupling protein 2 in the glial response to stress: Implications for neuroprotection, Neural Regen. Res., 11, 1197, 10.4103/1673-5374.189159