Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases - PubMed (original) (raw)
Review
Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Stéphane Demine et al. Cells. 2019.
Abstract
Mitochondrial uncoupling can be defined as a dissociation between mitochondrial membrane potential generation and its use for mitochondria-dependent ATP synthesis. Although this process was originally considered a mitochondrial dysfunction, the identification of UCP-1 as an endogenous physiological uncoupling protein suggests that the process could be involved in many other biological processes. In this review, we first compare the mitochondrial uncoupling agents available in term of mechanistic and non-specific effects. Proteins regulating mitochondrial uncoupling, as well as chemical compounds with uncoupling properties are discussed. Second, we summarize the most recent findings linking mitochondrial uncoupling and other cellular or biological processes, such as bulk and specific autophagy, reactive oxygen species production, protein secretion, cell death, physical exercise, metabolic adaptations in adipose tissue, and cell signaling. Finally, we show how mitochondrial uncoupling could be used to treat several human diseases, such as obesity, cardiovascular diseases, or neurological disorders.
Keywords: adipocyte browning; apoptosis; autophagy; cell death; cell signaling; mitochondrial uncoupling; oxidative stress; physical exercise; protein secretion; uncoupler.
Conflict of interest statement
The authors declare no conflicts of interest.
Figures
Figure 1
Overview of the cellular consequences of mitochondrial uncoupling. Abbreviations: ADP (Adenosine DiPhosphate), AMPK (Adenosine Monophosphate-Activated Protein Kinase), ATP (Adenosine Triphosphate), ATPs (ATPsynthase), CytC (Cytochrome C), FFA (Free Fatty Acid), LD (Lipid Droplet), ROS (Reactive Oxygen Species), NAD (Nicotinamide Adenine Dinucleotide). Induction of mitochondrial uncoupling by use of synthetic or natural uncoupling agents or by activating dedicated proteins, such as UCPs or ANTs, can trigger several cellular mechanisms. The first effect, and the most well-known, is the inhibition of mitochondrial ATP production by ATP synthase due to the dissipation of the mitochondrial proton gradient. This energy will be dissipated as heat (thermogenesis). The decrease in cytosolic ATP will be sensed by AMPK and lead to its activation. In addition, the decrease in mitochondrial potential membrane will also modify ROS generation. In order to cope with this energy loss, autophagy will also be triggered (both bulk and specific forms of autophagy). Lipid droplets (LD) will be degraded by a form of autophagy and help to fuel the cell with lipids. Loss of the mitochondrial potential membrane will also allow the identification of these dysfunctional mitochondria by autophagy (mitophagy). Mitochondrial uncoupling can also help to protect cells against cell death and apoptosis but can also promote it, according to the cell type, mitochondrial uncoupler and mitochondrial uncoupling intensity considered. Finally, the use of non-specific mitochondrial uncouplers, such as FCCP or DNP, could alter the homeostasis of several ions, such as Ca2+, Na+ and K+ (at the cytosolic, mitochondria, or lysosomal levels), which will lead to a decrease in protein secretion and plasma membrane (de)polarization, respectively.
Figure 2
Effect of mitochondrial uncoupling proteins on mitochondrial ROS generation. Abbreviations: ANT-1 (Adenine Nucleotide Transferase-1), ATPs (ATPsynthase), IMS (Inter Membrane Space of Mitochondria), ROS (Reactive Oxygen Species), UCP-1 (Uncoupling Protein-1). Mitochondrial ATP production relies on the coupling between the proton gradient on either side of the inner mitochondrial membrane and the use of this proton-motive force to feed the mitochondrial ATP synthase complex. However, this coupling is not complete and could lead to the production of ROS. Many different ROS can be produced by the mitochondria, including superoxide anion (O2•−), which is dismuted into hydrogen peroxide (H2O2), and could generate peroxinitrite (ONOO-). Many other parameters can increase the ROS production rate, including change in cytosolic or mitochondrial pH, the redox cellular state, or high local O2 availability. UCP-1 is a protein specialized in proton transport across the inner mitochondrial membrane. By uncoupling the mitochondrial respiration, it decreases the ROS generation rate. Of note, this effect is likely to be dependent on cell type and species. At the opposite, the role of UCP-2 and UCP-3, two other members of UCP protein family but with a less defined proton transport capacity, is clearer and consists in ROS reduction. Activation of ANT-1 also leads to a decrease in ROS production. Of note, high ROS production will also lead to a cellular adaptation and to an increase in UCPs expression (dashed line).
Figure 3
Effect of exercise on mitochondrial uncoupling and peripheral organs. Abbreviations: ANT-1 (Adenine Nucletotide Transferase-1), BAT (Brown Adipose Tissue), UCP-1 (Uncoupling Protein-1), WAT (White Adipose Tissue). Different kinds of physical exercise (acute and chronic) trigger mitochondrial uncoupling in skeletal muscle, by activating and by increasing both UCP-1 and ANT-1 expression. Of note, molecular mechanisms triggered differ according to the species considered and are not yet entirely defined. Activation of mitochondrial uncoupling in skeletal muscle also reduces oxidative stress and induces mitochondrial adaptations (including increase in mitochondrial mass, increase in respiratory chain component abundance). Physical exercise also has an impact on adipose tissues. In BAT, mitochondrial uncoupling will be activated (UCP-1 dependent), while it will be attenuated in WAT. Browning of WAT will also be induced, an effect dependent, at least partially, on irisin secretion by skeletal muscle. An association between decreased Firmicutes level in gastrointestinal tract (associated with physical exercise) and WAT browning has also been observed. In case of sustained physical exercise, adipose tissue mass will decrease which will alleviate both oxidative stress and secretion of proinflammatory cytokines.
Figure 4
Regulation of browning of white adipocytes. Abbreviations: IL (Interleukin), UCP-1 (Uncoupling Protein-1). White adipocytes are a cell-type specialized in lipid storage but also characterized by an important endocrine function. These cells are characterized by an unilocular lipid droplet and a reduced mitochondrial mass. During the last decades, it was demonstrated that these cells could transdifferentiate into brown adipocytes under certain circumstances such as cold exposure, change in gut microbiota (decrease in Firmicutes level) or exposition to cytokine (such as IL-18), myokine (such as irisin) or chemical compounds (such as retinoic acid). This process can be inhibited by several conditions including exposition to proinflammatory cytokines such as IL-6 or IL-1β or to oxidative stress. A more detailed list of pro/anti-browning conditions can be found in the main text. The adipocyte browning is characterized by an increase in lipogenesis and changes in terms of lipid droplet number and composition. The hallmark of adipocyte browning is the induction of UCP-1 expression. Of note, if it is considered that adipocyte browning is accompanied by UCP-1 activation, it was recently suggested that UCP-1 could also play a key role in lipid metabolism. Activation of UCP-1 is often accompanied by a decrease in oxidative stress in adipose tissues. Brown adipocytes can also differentiate into white adipocytes. This process, named adipose tissue whitening, is accompanied an increase in mitophagy in order to clear cells from UCP-1 expressing mitochondria.
Figure 5
Systemic effect of mitochondrial uncouplers on different organs in the context of obesity and type 2 diabetes. Abbreviations: HDL (High Density Lipoprotein), IFNγ (Interferon γ), IL (Interleukin), MCP-1 (Monocyte Chemoattractant Protein-1), NAFLD (Non-Alcoholic Fatty Liver Disease), NPY (Neuropeptide Y), POMC (Proopiomelanocortin), TAG (Triacylglycerol), TNF-α (Tumor Necrosis Factor-α). Use of systemic mitochondrial uncouplers, such as DNP or FCCP, will impact the functions of multiples organs. Some of these effects could be beneficial for the treatment of obesity and associated complications, such as type 2 diabetes. First, the global mitochondrial uncoupling induced by these molecules and the subsequent increase in cell respiration will increase global energy expenditure. As a consequence, lipid stores of different organs will be mobilized (increase in lipolysis, decrease in lipogenesis, and decrease in total TAG content and circulating levels). A global decrease in lipid stores will also help to alleviate the proinflammatory state seen in adipose tissues of obese patients. Patients will also be protected against NAFLD. Mitochondrial uncouplers also exert a direct effect on the brain and could affect the activity of NPY (decrease) and POMC (increase) neuron activity. Finally, it is important to stress that excessive mitochondrial uncoupling (due to excessive dosage and/or sensitivity to these compounds) will induce many complications, such as acute cataract, sensory axonal polyneuropathy, fever, tachycardia, sweating, nausea, rash, breathing difficulties, abdominal pain, agitation, headache, and, ultimately, death. Therefore, if mitochondrial uncoupling induction could be beneficial, it should be achieved by using highly mitochondria-specific and safe compounds, which remain to be developed.
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