S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver
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 syn...
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| Veröffentlicht in: | Journal of bioenergetics and biomembranes 2021-10, Vol.53 (5), p.525-539 |
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| creator | Seminotti, Bianca Roginski, Ana Cristina Zanatta, Ângela Amaral, Alexandre Umpierrez Fernandes, Thabata Spannenberger, Kaleb Pinto da Silva, Lucas Henrique Rodrigues Ribeiro, Rafael Teixeira Leipnitz, Guilhian Wajner, Moacir |
| description | 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 Ca
2+
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. |
| doi_str_mv | 10.1007/s10863-021-09914-3 |
| format | Article |
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2+
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.</description><identifier>ISSN: 0145-479X</identifier><identifier>EISSN: 1573-6881</identifier><identifier>DOI: 10.1007/s10863-021-09914-3</identifier><identifier>PMID: 34347214</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adenosine ; Adenosine diphosphate ; Adenosine kinase ; Adenosylmethionine ; Alkylation ; Animal Anatomy ; Animal Biochemistry ; Animals ; Bioaccumulation ; Biochemistry ; Bioorganic Chemistry ; Calcium (mitochondrial) ; Calcium ions ; Chemistry ; Chemistry and Materials Science ; Cyclosporin A ; Damage accumulation ; Depletion ; Free radicals ; Glycine ; Glycine N-methyltransferase ; Histology ; Homeostasis ; Hydrolase ; Ketoglutaric acid ; Kinases ; Lipid peroxidation ; Lipids ; Liver ; Liver - pathology ; Liver diseases ; Male ; Membrane permeability ; Membrane potential ; Metabolites ; Methyltransferase ; Mitochondrial DNA ; Mitochondrial Membrane Transport Proteins - drug effects ; Mitochondrial permeability transition pore ; Morphology ; N-Methyltransferase ; Organic Chemistry ; Oxidation ; Oxidation-Reduction - drug effects ; Oxoglutarate dehydrogenase (lipoamide) ; Pathogenesis ; Permeability ; Peroxidation ; Rats ; Rats, Wistar ; Retention capacity ; S-Adenosylmethionine ; S-Adenosylmethionine - adverse effects</subject><ispartof>Journal of bioenergetics and biomembranes, 2021-10, Vol.53 (5), p.525-539</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-a103e1ff7430d4ce31ef46243a53a6e94f974a4cfd60c05fd3e235f4a90c0b633</citedby><cites>FETCH-LOGICAL-c375t-a103e1ff7430d4ce31ef46243a53a6e94f974a4cfd60c05fd3e235f4a90c0b633</cites><orcidid>0000-0001-5814-6369 ; 0000-0001-7964-8923 ; 0000-0001-6512-0714 ; 0000-0001-6372-1807 ; 0000-0002-3405-3739 ; 0000-0002-9803-7746</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10863-021-09914-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10863-021-09914-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34347214$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seminotti, Bianca</creatorcontrib><creatorcontrib>Roginski, Ana Cristina</creatorcontrib><creatorcontrib>Zanatta, Ângela</creatorcontrib><creatorcontrib>Amaral, Alexandre Umpierrez</creatorcontrib><creatorcontrib>Fernandes, Thabata</creatorcontrib><creatorcontrib>Spannenberger, Kaleb Pinto</creatorcontrib><creatorcontrib>da Silva, Lucas Henrique Rodrigues</creatorcontrib><creatorcontrib>Ribeiro, Rafael Teixeira</creatorcontrib><creatorcontrib>Leipnitz, Guilhian</creatorcontrib><creatorcontrib>Wajner, Moacir</creatorcontrib><title>S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver</title><title>Journal of bioenergetics and biomembranes</title><addtitle>J Bioenerg Biomembr</addtitle><addtitle>J Bioenerg Biomembr</addtitle><description>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 Ca
2+
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.</description><subject>Adenosine</subject><subject>Adenosine diphosphate</subject><subject>Adenosine kinase</subject><subject>Adenosylmethionine</subject><subject>Alkylation</subject><subject>Animal Anatomy</subject><subject>Animal Biochemistry</subject><subject>Animals</subject><subject>Bioaccumulation</subject><subject>Biochemistry</subject><subject>Bioorganic Chemistry</subject><subject>Calcium (mitochondrial)</subject><subject>Calcium ions</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Cyclosporin A</subject><subject>Damage accumulation</subject><subject>Depletion</subject><subject>Free radicals</subject><subject>Glycine</subject><subject>Glycine N-methyltransferase</subject><subject>Histology</subject><subject>Homeostasis</subject><subject>Hydrolase</subject><subject>Ketoglutaric acid</subject><subject>Kinases</subject><subject>Lipid peroxidation</subject><subject>Lipids</subject><subject>Liver</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Membrane permeability</subject><subject>Membrane potential</subject><subject>Metabolites</subject><subject>Methyltransferase</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial Membrane Transport Proteins - drug effects</subject><subject>Mitochondrial permeability transition pore</subject><subject>Morphology</subject><subject>N-Methyltransferase</subject><subject>Organic Chemistry</subject><subject>Oxidation</subject><subject>Oxidation-Reduction - drug effects</subject><subject>Oxoglutarate dehydrogenase (lipoamide)</subject><subject>Pathogenesis</subject><subject>Permeability</subject><subject>Peroxidation</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Retention capacity</subject><subject>S-Adenosylmethionine</subject><subject>S-Adenosylmethionine - adverse 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induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver</title><author>Seminotti, Bianca ; Roginski, Ana Cristina ; Zanatta, Ângela ; Amaral, Alexandre Umpierrez ; Fernandes, Thabata ; Spannenberger, Kaleb Pinto ; da Silva, Lucas Henrique Rodrigues ; Ribeiro, Rafael Teixeira ; Leipnitz, Guilhian ; Wajner, Moacir</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-a103e1ff7430d4ce31ef46243a53a6e94f974a4cfd60c05fd3e235f4a90c0b633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenosine</topic><topic>Adenosine diphosphate</topic><topic>Adenosine kinase</topic><topic>Adenosylmethionine</topic><topic>Alkylation</topic><topic>Animal Anatomy</topic><topic>Animal Biochemistry</topic><topic>Animals</topic><topic>Bioaccumulation</topic><topic>Biochemistry</topic><topic>Bioorganic Chemistry</topic><topic>Calcium (mitochondrial)</topic><topic>Calcium ions</topic><topic>Chemistry</topic><topic>Chemistry and Materials Science</topic><topic>Cyclosporin A</topic><topic>Damage accumulation</topic><topic>Depletion</topic><topic>Free radicals</topic><topic>Glycine</topic><topic>Glycine N-methyltransferase</topic><topic>Histology</topic><topic>Homeostasis</topic><topic>Hydrolase</topic><topic>Ketoglutaric acid</topic><topic>Kinases</topic><topic>Lipid peroxidation</topic><topic>Lipids</topic><topic>Liver</topic><topic>Liver - pathology</topic><topic>Liver diseases</topic><topic>Male</topic><topic>Membrane permeability</topic><topic>Membrane potential</topic><topic>Metabolites</topic><topic>Methyltransferase</topic><topic>Mitochondrial DNA</topic><topic>Mitochondrial Membrane Transport Proteins - drug effects</topic><topic>Mitochondrial permeability transition pore</topic><topic>Morphology</topic><topic>N-Methyltransferase</topic><topic>Organic Chemistry</topic><topic>Oxidation</topic><topic>Oxidation-Reduction - drug effects</topic><topic>Oxoglutarate dehydrogenase (lipoamide)</topic><topic>Pathogenesis</topic><topic>Permeability</topic><topic>Peroxidation</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Retention capacity</topic><topic>S-Adenosylmethionine</topic><topic>S-Adenosylmethionine - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seminotti, Bianca</creatorcontrib><creatorcontrib>Roginski, Ana Cristina</creatorcontrib><creatorcontrib>Zanatta, Ângela</creatorcontrib><creatorcontrib>Amaral, Alexandre Umpierrez</creatorcontrib><creatorcontrib>Fernandes, Thabata</creatorcontrib><creatorcontrib>Spannenberger, Kaleb Pinto</creatorcontrib><creatorcontrib>da Silva, Lucas Henrique Rodrigues</creatorcontrib><creatorcontrib>Ribeiro, Rafael Teixeira</creatorcontrib><creatorcontrib>Leipnitz, Guilhian</creatorcontrib><creatorcontrib>Wajner, 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and biomembranes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seminotti, Bianca</au><au>Roginski, Ana Cristina</au><au>Zanatta, Ângela</au><au>Amaral, Alexandre Umpierrez</au><au>Fernandes, Thabata</au><au>Spannenberger, Kaleb Pinto</au><au>da Silva, Lucas Henrique Rodrigues</au><au>Ribeiro, Rafael Teixeira</au><au>Leipnitz, Guilhian</au><au>Wajner, Moacir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver</atitle><jtitle>Journal of bioenergetics and biomembranes</jtitle><stitle>J Bioenerg Biomembr</stitle><addtitle>J Bioenerg Biomembr</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>53</volume><issue>5</issue><spage>525</spage><epage>539</epage><pages>525-539</pages><issn>0145-479X</issn><eissn>1573-6881</eissn><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 Ca
2+
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.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34347214</pmid><doi>10.1007/s10863-021-09914-3</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-5814-6369</orcidid><orcidid>https://orcid.org/0000-0001-7964-8923</orcidid><orcidid>https://orcid.org/0000-0001-6512-0714</orcidid><orcidid>https://orcid.org/0000-0001-6372-1807</orcidid><orcidid>https://orcid.org/0000-0002-3405-3739</orcidid><orcidid>https://orcid.org/0000-0002-9803-7746</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0145-479X |
| ispartof | Journal of bioenergetics and biomembranes, 2021-10, Vol.53 (5), p.525-539 |
| issn | 0145-479X 1573-6881 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2558091445 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adenosine Adenosine diphosphate Adenosine kinase Adenosylmethionine Alkylation Animal Anatomy Animal Biochemistry Animals Bioaccumulation Biochemistry Bioorganic Chemistry Calcium (mitochondrial) Calcium ions Chemistry Chemistry and Materials Science Cyclosporin A Damage accumulation Depletion Free radicals Glycine Glycine N-methyltransferase Histology Homeostasis Hydrolase Ketoglutaric acid Kinases Lipid peroxidation Lipids Liver Liver - pathology Liver diseases Male Membrane permeability Membrane potential Metabolites Methyltransferase Mitochondrial DNA Mitochondrial Membrane Transport Proteins - drug effects Mitochondrial permeability transition pore Morphology N-Methyltransferase Organic Chemistry Oxidation Oxidation-Reduction - drug effects Oxoglutarate dehydrogenase (lipoamide) Pathogenesis Permeability Peroxidation Rats Rats, Wistar Retention capacity S-Adenosylmethionine S-Adenosylmethionine - adverse effects |
| title | S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver |
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