Interaction of 1,3,4-thiadiazolium mesoionic derivatives with mitochondrial membrane and scavenging activity: Involvement of their effects on mitochondrial energy-linked functions

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• 作者：Amanda do Rocio Andrade Pires^a ; Guilhermina Rodrigues Noleto^a ; Aurea Echevarria^b ; Camilla Moretto dos Reis^b ; Maria Eliane Merlin Rocha^a ; Eva Gunilla Skare Carnieri^a ; Glaucia Regina Martinez^a ; Silvia Maria Suter Correia Cadena^a ; ^{silvia.cadena@ufpr.br}
• 关键词：1 ; 3 ; 4-Thiadiazolium mesoionics ; Liver mitochondria ; Lipid peroxidation ; Mitochondrial swelling ; Fluorescence polarization
• 刊名：Chemico-Biological Interactions
• 出版年：2011
• 出版时间：15 January 2011
• 年：2011
• 卷：189
• 期：1-2
• 页码：17-25
• 全文大小：874 K

文摘

The aim of this work was to assess the significance of the interaction of the 1,3,4-thiadiazolium derivatives MI-J, MI-4F and MI-2,4diF with mitochondrial membrane and their effects on energy-linked functions. Mitochondrial swelling in the absence of substrate was inhibited by all derivatives; however, the fluorine derivatives were most effective. MI-4F decreased swelling by 32 % even at the lowest concentration (65 nmol mg⁻¹ protein), reaching 67 % at the concentration of 130 nmol mg⁻¹ protein. Swelling of mitochondria in the presence of oxidizable substrates was also strongly decreased by all derivatives. This effect was more pronounced when using glutamate plus malate, and also fluorine derivatives, which promoted complete inhibition at all concentrations (6.5–130 nmol mg⁻¹ protein). Swelling occurred when succinate was the substrate in the presence of MI-J (6.5–65 nmol mg⁻¹ protein); however, the shrinkage rate was strongly decreased. MI-4F and MI-2,4diF also inhibited swelling, with total inhibition occurring at a concentration of 65 nmol mg⁻¹ protein. Lipid peroxidation induced by Fe³⁺–ADP/2-oxoglutarate in isolated mitochondria was inhibited time- and dose-dependently by the derivatives, reaching complete inhibition at the highest concentration (80 nmol mg⁻¹ protein). However, when lipid peroxidation was initiated by peroxyl radicals generated from AAPH, the inhibition was less intense, reaching 50 % , 40 % and 58 % with MI-J, MI-4F and MI-2,4diF (80 nmol mg⁻¹ protein), respectively. The mesoionic compounds also showed superoxide radical scavenging ability of 22 % , 32 % and 40 % (80 nmol mg⁻¹ protein), respectively. Fluorescence polarization experiments showed that the derivatives are able to enter the bilayer, decreasing its fluidity in the hydrophobic DMPC membrane region and ordering the fluid phase. Our results suggest that MI-J, MI-4F and MI-2,4diF interact significantly, albeit in different modes, with mitochondrial membrane, and that fluorine derivatives seem to alter the membrane's properties more markedly.