Neuroprotective Potential of Mild Uncoupling in Mitochondria. Pros and Cons

Abstract

There has been an explosion of interest in the use of uncouplers of oxidative phosphorylation in mitochondria in the treatment of several pathologies, including neurological ones. In this review, we analyzed all the mechanisms associated with mitochondrial uncoupling and the metabolic and signaling cascades triggered by uncouplers. We provide a full set of positive and negative effects that should be taken into account when using uncouplers in experiments and clinical practice.

Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action

“…However, in this review, of great importance is not the industrial application of protonophores but their potential significance for pharmacology. After many years of studying protonophores, a lot of data about their protective properties have been collected through animal disease models: they may be used as cardioprotectors [ 88 ], neuroprotectors [ 73 , 89 ], nephroprotectors [ 90 ], radioprotectors [ 91 ], and exhibit antidiabetic activities [ 75 , 92 , 93 ], and the list goes on. Uncouplers may be used as anticancer agents [ 94 ].…”

“…As mentioned above, this protective effect is due to the ability of uncouplers to suppress the formation of ROS in mitochondria, which is largely controlled by the membrane potential [ 98 ]. Recent studies suggest that a decrease in the mitochondrial membrane potential in cells due to low concentrations of uncouplers may trigger a whole cascade of changes in the cell metabolism, which may lead to an increase in the mitochondrial mass in some cells [ 99 , 100 ], activation of mitophagy [ 101 ], changes in the ratio of glycolysis to oxidative phosphorylation [ 102 ], and many others [ 89 , 103 ]. The important role of calcium and cAMP in the alteration of cell metabolism is confirmed by the results of many studies [ 73 , 100 , 101 , 102 , 103 ].…”

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons

“…Concerning proton leak, the co-treatment with IGF-II and both drugs prevented its increase, improving mitochondrial efficiency [ 65 ], probably through the preservation of membrane oxidation and/or uncoupling protein modulation. The antioxidant functions of mild uncouplers, i.e., compounds that uncouple the processes of phosphorylation and mitochondrial electron transport and that ultimately maintain the ATP at an adequate level to meet cell metabolic demands, have led to an explosion of interest in the use of these molecules in the treatment of several pathologies, including neurological disorders at present [ 66 ]. Our previous study did not suggest the role of IGF-II as a mild uncoupler or a conventional antioxidant molecule, because the effects of IGF-II depend on its interaction with IGF-IIR [ 24 ].…”

“…Our previous study did not suggest the role of IGF-II as a mild uncoupler or a conventional antioxidant molecule, because the effects of IGF-II depend on its interaction with IGF-IIR [ 24 ]. However, IGF-II could modulate possible mild uncouplers [ 66 ]; specific studies are needed to confirm this hypothesis. Similarly, to compare IGF-II neuroprotection to the role of conventional antioxidants, experiments indicating whether IGF-II can act as a conventional antioxidant should be carried out.…”

Mechanisms of low-temperature rehabilitation technologies. Extreme aerocriotherapy

“…Представитель этого класса белков UCP1 благодаря способности к энергичному усилению метаболической активности получил название термогенин [15]. Белки UCP стимулируют синаптогенез, нейрогенез и нейропластичность, обладают антиоксидантными свойствами [16]. Под действием UCP1 повышается экспрессия мозгового нейротрофического фактора (brain-derived neurotrophic factor, BDNF) [17].…”