Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox SignalingReviewing Editors:Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

Abstract

Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling.Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells.Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling.Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714.

Plant Mitochondrial Carriers: Molecular Gatekeepers That Help to Regulate Plant Central Carbon Metabolism

“…Uncoupling proteins (UCPs) are suggested to mediate a non-phosphorylating free fatty acid-activated proton re-entry into the MM leading to a thermogenic dissipation of proton gradients, thereby uncoupling oxidative phosphorylation [61,70]. In animals, the protonophoretic function of UCP1 in brown adipose tissues leading to thermogenesis is of great importance among newborns, cold-acclimated, and hibernating mammals [71,72].…”

Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function

“…In addition, our study also shows a persistent increase in the rate of oxygen consumption at state 4 respiration, (a surrogate measure of proton leak) in young adults exposed to hyperoxia as neonates, and suggest uncoupling between substrate oxidation and ATP synthesis. Alterations in mitochondrial coupling can result in increased ROS production [36][37][38] and impairment in ATP synthesis 39 . Though the amount of ATP produced by the hippocampal tissue was not measured in this study, the decrease in ATP linked oxygen consumption and increase in state 4 proton leak both at P14 and 14 weeks suggest that early life 1 1 oxygen exposure permanently impairs mitochondrial efficiency in the generation of ATP.…”

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

“…However, this mechanism is less probable in mitochondria. Nevertheless, as an example, one may recall a sudden inhibition of uncoupling provided otherwise by the mitochondrial uncoupling proteins (UCP) [14,15]. Such an inhibition would result in providing a slight surplus of superoxide, since before the inhibition of UCPs, its formation is suppressed by uncoupling of respiratory chain proton pumping from the proton backflow through the c-ring of the mitochondrial ATP-synthase.…”

“…The whole protonmotive force is consumed physiologically by H + backflow from the ICS back to the matrix via the c-ring of membrane F O -sector of ATP-synthase. When active, mitochondrial uncoupling proteins partly or substantially consume ∆p (its both components, ∆Ψ m and ∆pH) and attenuate ∆Ψ m -dependent superoxide formation [14,15]. However, non-zero membrane H + permeability termed as H + leak permanently acts against the established ∆p.…”