Abstract
S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, as well as in some hepatic mtDNA depletion syndromes, whose pathogenesis of liver dysfunction is still poorly established. Therefore, in the present work, we investigated the effects of S-adenosylmethionine (AdoMet) on mitochondrial functions and redox homeostasis in rat liver. AdoMet decreased mitochondrial membrane potential and Ca2+ retention capacity, and these effects were fully prevented by cyclosporin A and ADP, indicating mitochondrial permeability transition (mPT) induction. It was also verified that the thiol-alkylating agent NEM prevented AdoMet-induced ΔΨm dissipation, implying a role for thiol oxidation in the mPT pore opening. AdoMet also increased ROS production and provoked protein and lipid oxidation. Furthermore, AdoMet reduced GSH levels and the activities of aconitase and α-ketoglutarate dehydrogenase. Free radical scavengers attenuated AdoMet effects on lipid peroxidation and GSH levels, supporting a role of ROS in these effects. It is therefore presumed that disturbance of mitochondrial functions associated with mPT and redox unbalance may represent relevant pathomechanisms of liver damage provoked by AdoMet in disorders in which this metabolite accumulates.
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This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência (FINEP) and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).
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This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq, Grant #425914/2016-0], Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul [FAPERGS, Grant #2266-2551/14-2], Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência [FINEP, Grant #01.06.0842-00] and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção [INCT-EN, Grant #573677/2008-5].
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BS, ACR, AZ and MW conceived the project and designed the experiments. BS, ACR, AZ, TF, KPS, LHRS and RTR performed the experiments and collected the data. BS, ACR, AUA, GL and MW analysed the data. BS, AUA, GL and MW co-wrote the paper. All authors discussed the results and reviewed the manuscript.
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Seminotti, B., Roginski, A.C., Zanatta, Â. et al. S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver. J Bioenerg Biomembr 53, 525–539 (2021). https://doi.org/10.1007/s10863-021-09914-3
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DOI: https://doi.org/10.1007/s10863-021-09914-3