Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study
Abstract Background Diabetic cardiomyopathy (DCM) has been considered as a major threat to health in individuals with diabetes. GrpE-like 2 (Grpel2), a nucleotide exchange factor, has been shown to regulate mitochondrial import process to maintain mitochondrial homeostasis. However, the effect and m...
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04049-y |
| _version_ | 1797863650302623744 |
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| author | Rongjin Yang Xiaomeng Zhang Yunyun Zhang Yingfan Wang Man Li Yuancui Meng Jianbang Wang Xue Wen Jun Yu Pan Chang |
| author_facet | Rongjin Yang Xiaomeng Zhang Yunyun Zhang Yingfan Wang Man Li Yuancui Meng Jianbang Wang Xue Wen Jun Yu Pan Chang |
| author_sort | Rongjin Yang |
| collection | DOAJ |
| description | Abstract Background Diabetic cardiomyopathy (DCM) has been considered as a major threat to health in individuals with diabetes. GrpE-like 2 (Grpel2), a nucleotide exchange factor, has been shown to regulate mitochondrial import process to maintain mitochondrial homeostasis. However, the effect and mechanism of Grpel2 in DCM remain unknown. Methods The streptozotocin (STZ)-induced DCM mice model and high glucose (HG)-treated cardiomyocytes were established. Overexpression of cardiac-specific Grpel2 was performed by intramyocardial injection of adeno-associated virus serotype 9 (AAV9). Bioinformatics analysis, co-immunoprecipitation (co-IP), transcriptomics profiling and functional experiments were used to explore molecular mechanism of Grpel2 in DCM. Results Here, we found that Grpel2 was decreased in DCM induced by STZ. Overexpression of cardiac-specific Grpel2 alleviated cardiac dysfunction and structural remodeling in DCM. In both diabetic hearts and HG-treated cardiomyocytes, Grpel2 overexpression attenuated apoptosis and mitochondrial dysfunction, including decreased mitochondrial ROS production, increased mitochondrial respiratory capacities and increased mitochondrial membrane potential. Mechanistically, Grpel2 interacted with dihydrolipoyl succinyltransferase (DLST), which positively mediated the import process of DLST into mitochondria under HG conditions. Furthermore, the protective effects of Grpel2 overexpression on mitochondrial function and cell survival were blocked by siRNA knockdown of DLST. Moreover, Nr2f6 bond to the Grpel2 promoter region and positively regulated its transcription. Conclusion Our study provides for the first time evidence that Grpel2 overexpression exerts a protective effect against mitochondrial dysfunction and apoptosis in DCM by maintaining the import of DLST into mitochondria. These findings suggest that targeting Grpel2 might be a promising therapeutic strategy for the treatment of patients with DCM. |
| first_indexed | 2024-04-09T22:40:06Z |
| format | Article |
| id | doaj.art-0d3d2b432bf840208c7c5272c40ede6f |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T22:40:06Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-0d3d2b432bf840208c7c5272c40ede6f2023-03-22T12:14:19ZengBMCJournal of Translational Medicine1479-58762023-03-0121112110.1186/s12967-023-04049-yGrpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept studyRongjin Yang0Xiaomeng Zhang1Yunyun Zhang2Yingfan Wang3Man Li4Yuancui Meng5Jianbang Wang6Xue Wen7Jun Yu8Pan Chang9Department of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityDepartment of Cardiology, Xijing Hospital, Air Force Medical UniversityDepartment of Cardiology, Xijing Hospital, Air Force Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityDepartment of Cardiology, The 989th Hospital of the People’s Liberation Army Joint Logistic Support ForceClinical Experimental Center, The Affiliated Xi’an International Medical Center Hospital, Northwest UniversityDepartment of Cardiology, The Second Affiliated Hospital of Xi’an Medical UniversityAbstract Background Diabetic cardiomyopathy (DCM) has been considered as a major threat to health in individuals with diabetes. GrpE-like 2 (Grpel2), a nucleotide exchange factor, has been shown to regulate mitochondrial import process to maintain mitochondrial homeostasis. However, the effect and mechanism of Grpel2 in DCM remain unknown. Methods The streptozotocin (STZ)-induced DCM mice model and high glucose (HG)-treated cardiomyocytes were established. Overexpression of cardiac-specific Grpel2 was performed by intramyocardial injection of adeno-associated virus serotype 9 (AAV9). Bioinformatics analysis, co-immunoprecipitation (co-IP), transcriptomics profiling and functional experiments were used to explore molecular mechanism of Grpel2 in DCM. Results Here, we found that Grpel2 was decreased in DCM induced by STZ. Overexpression of cardiac-specific Grpel2 alleviated cardiac dysfunction and structural remodeling in DCM. In both diabetic hearts and HG-treated cardiomyocytes, Grpel2 overexpression attenuated apoptosis and mitochondrial dysfunction, including decreased mitochondrial ROS production, increased mitochondrial respiratory capacities and increased mitochondrial membrane potential. Mechanistically, Grpel2 interacted with dihydrolipoyl succinyltransferase (DLST), which positively mediated the import process of DLST into mitochondria under HG conditions. Furthermore, the protective effects of Grpel2 overexpression on mitochondrial function and cell survival were blocked by siRNA knockdown of DLST. Moreover, Nr2f6 bond to the Grpel2 promoter region and positively regulated its transcription. Conclusion Our study provides for the first time evidence that Grpel2 overexpression exerts a protective effect against mitochondrial dysfunction and apoptosis in DCM by maintaining the import of DLST into mitochondria. These findings suggest that targeting Grpel2 might be a promising therapeutic strategy for the treatment of patients with DCM.https://doi.org/10.1186/s12967-023-04049-yDiabetic cardiomyopathyDLSTGrpel2Mitochondrial dysfunctionNr2f6 |
| spellingShingle | Rongjin Yang Xiaomeng Zhang Yunyun Zhang Yingfan Wang Man Li Yuancui Meng Jianbang Wang Xue Wen Jun Yu Pan Chang Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study Journal of Translational Medicine Diabetic cardiomyopathy DLST Grpel2 Mitochondrial dysfunction Nr2f6 |
| title | Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study |
| title_full | Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study |
| title_fullStr | Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study |
| title_full_unstemmed | Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study |
| title_short | Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study |
| title_sort | grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through dlst mediated mitochondrial dysfunction a proof of concept study |
| topic | Diabetic cardiomyopathy DLST Grpel2 Mitochondrial dysfunction Nr2f6 |
| url | https://doi.org/10.1186/s12967-023-04049-y |
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