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.
Highlights
According to the chemiosmotic theory developed by Peter Mitchell, mitochondrial electron transfer is accompanied by proton fluxes and coupled through the redox proton pumps mediated by mitochondrial complexes (CI, CIII, and CIV) [1]
20) were observed in HeLa cells exposed to CCCP (20 μM, 24 h), suggesting that mitochondrial morphology and structure are severely affected by the mitochondrial uncoupler [83], and that mitochondrial clearance induced by CCCP is not complete
The most well-known effect of mitochondrial depolarization induced by protonophores such as FCCP or CCCP is the promotion of mitochondrial degradation by autophagy
Summary
According to the chemiosmotic theory developed by Peter Mitchell, mitochondrial electron transfer is accompanied by proton fluxes and coupled through the redox proton pumps mediated by mitochondrial complexes (CI, CIII, and CIV) [1]. Not all potential energy is transformed/converted into ATP by the mitochondrial rotor, as some degree of uncoupling relative to the substrate-dependent coupling stoichiometry is observed during electrochemical energy transformation into ATP. This incomplete coupling can be explained by several processes: basal and inducible proton leak, electron leak, and electron slip. Protons can directly escape from the inner mitochondrial space by diffusion through the inner mitochondrial membrane, a process named basal proton leak. Of the resting cellular metabolic rate [3] This process can be regulated/induced by a dedicated set of proteins: UCPs (Uncoupling Proteins) or ANTs (Adenine Nucleotide Translocases). We will cover recent advances in the understanding of the effects of natural and artificial mitochondrial uncoupling in the regulation of biological processes and diseases such as obesity, cardiovascular diseases, or neurological disorders
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