Title (eng)
The role of the solute carrier 25 proteins in fatty acid and 2,4-dinitrophenol-mediated proton transport
Author
Degree supervisor
Elena E. Pohl
Mario Vazdar
Description (eng)
PhD thesis - University of Veterinary Medicine Vienna - 2024
Abstract (eng)
By enhancing metabolic efficiency and counteracting harmful reactive oxygen species, uncoupling is a promising strategy for preventing and treating metabolic diseases such as obesity and type II diabetes. It involves the dissipation of mitochondrial membrane potential (MMP) through proton transport, independent of ATP production. Physiologically, uncoupling is facilitated by free fatty acids (FAs) and enhanced by various members of the solute carrier 25 (SLC25) protein family. Chemically synthesized uncoupling agents like 2,4-dinitrophenol (DNP) also exhibit potent protonophoric effects, demonstrating efficacy in weight loss and inhibition of cancer cell proliferation. Nonetheless, the intricate interaction between protonophores and proteins remains poorly understood, particularly regarding the uncoupling potential of individual SLC25 family members. Among these proteins is the 2-oxoglutarate/malate carrier (OGC), a pivotal component in mitochondrial energy creation. To test how natural and chemical uncouplers affect proteins, we produced several SLC25 family members and incorporated them into proteoliposomes. By measuring the conductance, we demonstrated that adenine nucleotide translocase (ANT1) and uncoupling proteins 1-3 (UCP1-3) significantly enhance the protonophoric effect of DNP. Notably, we provide novel evidence confirming the involvement of the 2-oxoglutarate/malate carrier (OGC) in uncoupling, similar to ANT1 and UCPs, in the presence of FAs and DNP. Furthermore, we found that ANT1’s uncoupling pattern points to the FA cycling model and that reactive alkenals, products of oxidative damage, reshape membrane lipids and indirectly increase uncoupling mediated by SLC25 carriers. Based on our results, we propose that during high-energy demand, mitochondrial carriers support ATP production by transporting substrates in and out of the mitochondrial matrix. Conversely, under low energy demand or oxidative stress, they facilitate proton transport through an increased concentration of FAs. The synergistic effect of SLC25 family transporters can result in a beneficial and transient decrease in MMP. Understanding the uncoupling mechanisms of these proteins can help selectively design new or enhance existing chemical uncouplers. This targeted approach can be used to induce desired physiological changes in specific tissues, providing a potential therapeutic strategy against various diseases.
Description (deu)
PhD Arbeit - Veterinärmedizinische Universität Wien - 2024
Type (eng)
Language
[eng]
Persistent identifier
AC number
Number of pages
117
Date issued
2024
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- DetailsResource typeText (PDF)Formatapplication/pdfCreated16.01.2026 08:57:23 UTC
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