SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM
Background and Purpose: Mitochondrial dysfunction remains the crucial cause for many heart diseases including diabetic cardiomyopathy (DCM). Sirtuin-3 (SIRT-3) is a protein deacetylase localized in the mitochondria and regulates mitochondrial function. Being a noteworthy mitochondrial protein deacet...
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MDPI AG
2018-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/7/12/235 |
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| author | Pankaj K. Bagul Parmeshwar B. Katare Paramesha Bugga Amit K. Dinda Sanjay K. Banerjee |
| author_facet | Pankaj K. Bagul Parmeshwar B. Katare Paramesha Bugga Amit K. Dinda Sanjay K. Banerjee |
| author_sort | Pankaj K. Bagul |
| collection | DOAJ |
| description | Background and Purpose: Mitochondrial dysfunction remains the crucial cause for many heart diseases including diabetic cardiomyopathy (DCM). Sirtuin-3 (SIRT-3) is a protein deacetylase localized in the mitochondria and regulates mitochondrial function. Being a noteworthy mitochondrial protein deacetylase enzyme, the role of SIRT-3 in DCM is yet to be explored. Experimental Approach: Diabetes mellitus (Type-I, T1DM) was induced using streptozotocin (STZ, 50 mg/kg) in male Sprague Dawley (SD) rats. Rats with >200 mg/dL blood glucose levels were then divided randomly into two groups, DIA and DIA + RESV, where vehicle and resveratrol (25 mg/kg/day) were administered orally in both groups, respectively. Cardiac oxidative stress, fibrosis, and mitochondrial parameters were evaluated. H9c2 cells were transfected with SIRT-3 siRNA and shRNA, and ORF plasmid for silencing and overexpression, respectively. Key Results: After eight weeks, diabetic rat heart showed reduced cardiac cell size, increased oxidative stress and reduction of the activities of enzymes involved in mitochondrial oxidative phosphorylation (OXPHOS). There was reduced expression and activity of SIRT-3 and mitochondrial transcription factor (TFAM) in diabetic heart. Reduced SIRT-3 expression is also correlated with increased acetylation, decreased mitochondrial DNA (mtDNA) binding activity of TFAM, and reduced transcription of mitochondrial DNA encoded genes. Administration of resveratrol prevented the decrease in SIRT-3 and TFAM activity, which was corresponding to the reduced acetylation status of TFAM. Silencing SIRT-3 using siRNA in H9C2 cells showed increased acetylation of TFAM. Conclusion and Implications: Together our data shows that resveratrol activates SIRT-3, regulates the acetylation status of TFAM and preserves the mitochondrial function along with cellular size in diabetic rat heart. |
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| spelling | doaj.art-08658d98ea77489fba8c90b80b2ea94d2023-09-03T09:50:47ZengMDPI AGCells2073-44092018-11-0171223510.3390/cells7120235cells7120235SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAMPankaj K. Bagul0Parmeshwar B. Katare1Paramesha Bugga2Amit K. Dinda3Sanjay K. Banerjee4Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad 121001, IndiaDrug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad 121001, IndiaDrug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad 121001, IndiaDepartment of Pathology, All India Institute of Medical Science (AIIMS), New Delhi 110029, IndiaDrug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad 121001, IndiaBackground and Purpose: Mitochondrial dysfunction remains the crucial cause for many heart diseases including diabetic cardiomyopathy (DCM). Sirtuin-3 (SIRT-3) is a protein deacetylase localized in the mitochondria and regulates mitochondrial function. Being a noteworthy mitochondrial protein deacetylase enzyme, the role of SIRT-3 in DCM is yet to be explored. Experimental Approach: Diabetes mellitus (Type-I, T1DM) was induced using streptozotocin (STZ, 50 mg/kg) in male Sprague Dawley (SD) rats. Rats with >200 mg/dL blood glucose levels were then divided randomly into two groups, DIA and DIA + RESV, where vehicle and resveratrol (25 mg/kg/day) were administered orally in both groups, respectively. Cardiac oxidative stress, fibrosis, and mitochondrial parameters were evaluated. H9c2 cells were transfected with SIRT-3 siRNA and shRNA, and ORF plasmid for silencing and overexpression, respectively. Key Results: After eight weeks, diabetic rat heart showed reduced cardiac cell size, increased oxidative stress and reduction of the activities of enzymes involved in mitochondrial oxidative phosphorylation (OXPHOS). There was reduced expression and activity of SIRT-3 and mitochondrial transcription factor (TFAM) in diabetic heart. Reduced SIRT-3 expression is also correlated with increased acetylation, decreased mitochondrial DNA (mtDNA) binding activity of TFAM, and reduced transcription of mitochondrial DNA encoded genes. Administration of resveratrol prevented the decrease in SIRT-3 and TFAM activity, which was corresponding to the reduced acetylation status of TFAM. Silencing SIRT-3 using siRNA in H9C2 cells showed increased acetylation of TFAM. Conclusion and Implications: Together our data shows that resveratrol activates SIRT-3, regulates the acetylation status of TFAM and preserves the mitochondrial function along with cellular size in diabetic rat heart.https://www.mdpi.com/2073-4409/7/12/235diabetic cardiomyopathytranscription factor Amitochondriaacetylation |
| spellingShingle | Pankaj K. Bagul Parmeshwar B. Katare Paramesha Bugga Amit K. Dinda Sanjay K. Banerjee SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM Cells diabetic cardiomyopathy transcription factor A mitochondria acetylation |
| title | SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM |
| title_full | SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM |
| title_fullStr | SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM |
| title_full_unstemmed | SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM |
| title_short | SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM |
| title_sort | sirt 3 modulation by resveratrol improves mitochondrial oxidative phosphorylation in diabetic heart through deacetylation of tfam |
| topic | diabetic cardiomyopathy transcription factor A mitochondria acetylation |
| url | https://www.mdpi.com/2073-4409/7/12/235 |
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