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.

Mitochondrial unfolded protein response is a form of retrograde signaling that contributes to ensuring the maintenance of quality control of mitochondria, allowing functional integrity of the mitochondrial proteome. When misfolded proteins or unassembled complexes accumulate beyond the folding capacity, it leads to alteration of proteostasis, damages, and organelle/cell dysfunction. Extensively studied for the ER, it was recently reported that this kind of signaling for mitochondrion would also be able to communicate with the nucleus in response to impaired proteostasis. The mitochondrial unfolded protein response (UPR^mt) is activated in response to different types and levels of stress, especially in conditions where unfolded or misfolded mitochondrial proteins accumulate and aggregate. A specific UPR^mt could thus be initiated to boost folding and degradation capacity in response to unfolded and aggregated protein accumulation. Although first described in mammals, the UPR^mt was mainly studied in Caenorhabditis elegans, and accumulating evidence suggests that mechanisms triggered in response to a UPR^mt might be different in C. elegans and mammals. In this review, we discuss and integrate recent data from the literature to address whether the UPR^mt is relevant to mitochondrial homeostasis in mammals and to analyze the putative role of integrated stress response (ISR) activation in response to the inhibition of mtDNA expression and/or accumulation of mitochondrial mis/unfolded proteins.

Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance. miRNAs have recently been shown to play important roles in tumorigenesis and drug resistance. Moreover, hypoxia also regulates the expression of a series of miRNAs. However, the interaction between chemoresistance, hypoxia and miRNAs has not been explored yet. The aim of this study is to understand the mechanisms activated/inhibited by miRNAs under hypoxia that induce resistance to chemotherapy-induced apoptosis. TaqMan low-density array was used to identify changes in miRNA expression when cells were exposed to etoposide under hypoxia or normoxia. The effects of miR-196b overexpression on apoptosis and cell proliferation were studied in HepG2 cells. miR-196b target mRNAs were identified by proteomic analysis, luciferase activity assay, RT-qPCR and western blot analysis. Results showed that hypoxia down-regulated miR-196b expression that was induced by etoposide. miR-196b overexpression increased the etoposide-induced apoptosis and reversed the protection of cell death observed under hypoxia. By a proteomic approach combined with bioinformatics analyses, we identified IGF2BP1 as a potential target of miR-196b. Indeed, miR-196b overexpression decreased IGF2BP1 RNA expression and protein level. The IGF2BP1 down-regulation by either miR-196b or IGF2BP1 siRNA led to an increase in apoptosis and a decrease in cell viability and proliferation in normal culture conditions. However, IGF2BP1 silencing did not modify the chemoresistance induced by hypoxia, probably because it is not the only target of miR-196b involved in the regulation of apoptosis. In conclusion, for the first time, we identified IGF2BP1 as a direct and functional target of miR-196b and showed that miR-196b overexpression reverses the chemoresistance induced by hypoxia. These results emphasize that the chemoresistance induced by hypoxia is a complex mechanism.