Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy
Background The mutated α‐B‐Crystallin (CryABR120G) mouse model of desmin‐related myopathy (DRM) shows an age‐dependent onset of pathologic cardiac remodeling and progression of heart failure. CryABR120G expression in cardiomyocytes affects the mitochondrial spatial organization within the myofibrils...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.017195 |
| _version_ | 1818775072052084736 |
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| author | Shafiul Alam Chowdhury S. Abdullah Richa Aishwarya Mahboob Morshed Sadia S. Nitu Sumitra Miriyala Manikandan Panchatcharam Christopher G. Kevil A. Wayne Orr Md. Shenuarin Bhuiyan |
| author_facet | Shafiul Alam Chowdhury S. Abdullah Richa Aishwarya Mahboob Morshed Sadia S. Nitu Sumitra Miriyala Manikandan Panchatcharam Christopher G. Kevil A. Wayne Orr Md. Shenuarin Bhuiyan |
| author_sort | Shafiul Alam |
| collection | DOAJ |
| description | Background The mutated α‐B‐Crystallin (CryABR120G) mouse model of desmin‐related myopathy (DRM) shows an age‐dependent onset of pathologic cardiac remodeling and progression of heart failure. CryABR120G expression in cardiomyocytes affects the mitochondrial spatial organization within the myofibrils, but the molecular perturbation within the mitochondria in the relation of the overall course of the proteotoxic disease remains unclear. Methods and Results CryABR120G mice show an accumulation of electron‐dense aggregates and myofibrillar degeneration associated with the development of cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause cardiac contractility impairment, the molecular mechanism of cardiomyocyte death remains elusive. Here, we explore early pathological processes within the mitochondria contributing to the contractile dysfunction and determine the pathogenic basis for the heart failure observed in the CryABR120G mice. In the present study, we report that the CryABR120G mice transgenic hearts undergo altered mitochondrial dynamics associated with increased level of dynamin‐related protein 1 and decreased level of optic atrophy type 1 as well as mitofusin 1 over the disease process. In association with these changes, an altered level of the components of mitochondrial oxidative phosphorylation and pyruvate dehydrogenase complex regulatory proteins occurs before the manifestation of pathologic adverse remodeling in the CryABR120G hearts. Mitochondria isolated from CryABR120G transgenic hearts without visible pathology show decreased electron transport chain complex activities and mitochondrial respiration. Taken together, we demonstrated the involvement of mitochondria in the pathologic remodeling and progression of DRM‐associated cellular dysfunction. Conclusions Mitochondrial dysfunction in the form of altered mitochondrial dynamics, oxidative phosphorylation and pyruvate dehydrogenase complex proteins level, abnormal electron transport chain complex activities, and mitochondrial respiration are evident on the CryABR120G hearts before the onset of detectable pathologies and development of cardiac contractile dysfunction. |
| first_indexed | 2024-12-18T10:51:13Z |
| format | Article |
| id | doaj.art-ccc0f1e6279442909ea7315916799405 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-18T10:51:13Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-ccc0f1e6279442909ea73159167994052022-12-21T21:10:26ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-12-0192310.1161/JAHA.120.017195Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related CardiomyopathyShafiul Alam0Chowdhury S. Abdullah1Richa Aishwarya2Mahboob Morshed3Sadia S. Nitu4Sumitra Miriyala5Manikandan Panchatcharam6Christopher G. Kevil7A. Wayne Orr8Md. Shenuarin Bhuiyan9Department of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Molecular and Cellular Physiology Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LADepartment of Cellular Biology and Anatomy Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LADepartment of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LABackground The mutated α‐B‐Crystallin (CryABR120G) mouse model of desmin‐related myopathy (DRM) shows an age‐dependent onset of pathologic cardiac remodeling and progression of heart failure. CryABR120G expression in cardiomyocytes affects the mitochondrial spatial organization within the myofibrils, but the molecular perturbation within the mitochondria in the relation of the overall course of the proteotoxic disease remains unclear. Methods and Results CryABR120G mice show an accumulation of electron‐dense aggregates and myofibrillar degeneration associated with the development of cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause cardiac contractility impairment, the molecular mechanism of cardiomyocyte death remains elusive. Here, we explore early pathological processes within the mitochondria contributing to the contractile dysfunction and determine the pathogenic basis for the heart failure observed in the CryABR120G mice. In the present study, we report that the CryABR120G mice transgenic hearts undergo altered mitochondrial dynamics associated with increased level of dynamin‐related protein 1 and decreased level of optic atrophy type 1 as well as mitofusin 1 over the disease process. In association with these changes, an altered level of the components of mitochondrial oxidative phosphorylation and pyruvate dehydrogenase complex regulatory proteins occurs before the manifestation of pathologic adverse remodeling in the CryABR120G hearts. Mitochondria isolated from CryABR120G transgenic hearts without visible pathology show decreased electron transport chain complex activities and mitochondrial respiration. Taken together, we demonstrated the involvement of mitochondria in the pathologic remodeling and progression of DRM‐associated cellular dysfunction. Conclusions Mitochondrial dysfunction in the form of altered mitochondrial dynamics, oxidative phosphorylation and pyruvate dehydrogenase complex proteins level, abnormal electron transport chain complex activities, and mitochondrial respiration are evident on the CryABR120G hearts before the onset of detectable pathologies and development of cardiac contractile dysfunction.https://www.ahajournals.org/doi/10.1161/JAHA.120.017195desmin‐related myopathymitochondrial dynamicsmitochondrial respirationoxidative phosphorylationR120G‐αB‐crystallin |
| spellingShingle | Shafiul Alam Chowdhury S. Abdullah Richa Aishwarya Mahboob Morshed Sadia S. Nitu Sumitra Miriyala Manikandan Panchatcharam Christopher G. Kevil A. Wayne Orr Md. Shenuarin Bhuiyan Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease desmin‐related myopathy mitochondrial dynamics mitochondrial respiration oxidative phosphorylation R120G‐αB‐crystallin |
| title | Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy |
| title_full | Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy |
| title_fullStr | Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy |
| title_full_unstemmed | Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy |
| title_short | Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G‐αB‐Crystallin‐Induced Desmin‐Related Cardiomyopathy |
| title_sort | dysfunctional mitochondrial dynamic and oxidative phosphorylation precedes cardiac dysfunction in r120g αb crystallin induced desmin related cardiomyopathy |
| topic | desmin‐related myopathy mitochondrial dynamics mitochondrial respiration oxidative phosphorylation R120G‐αB‐crystallin |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.017195 |
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