Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle
Abstract Aging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using qu...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04746-4 |
| _version_ | 1811272050365431808 |
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| author | Xue Lu Yingchao Gong Wanyu Hu Yankai Mao Ting Wang Zeyu Sun Xiaoling Su Guosheng Fu Yanpeng Wang Dongwu Lai |
| author_facet | Xue Lu Yingchao Gong Wanyu Hu Yankai Mao Ting Wang Zeyu Sun Xiaoling Su Guosheng Fu Yanpeng Wang Dongwu Lai |
| author_sort | Xue Lu |
| collection | DOAJ |
| description | Abstract Aging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using quantitative morphological analysis, we showed that the mitochondria-endoplasmic reticulum contacts (MERCs) were reduced by half over the lifespan with an early onset of accelerated thickening in the clefts. The ultrastructural changes were further validated by proteomic profiling of the MAM fractions. A combination of subcellular fractionation and quantitative mass spectrometry identified 1306 MAM-enriched proteins in both heart and skeletal muscle, with a catalog of proteins dysregulated with aging. Functional mapping of the MAM proteome suggested several aging signatures to be closely associated with the ER-mitochondria crosstalk, including local metabolic rewiring, calcium homeostasis imbalance, and impaired organelle dynamics and autophagy. Moreover, we identified a subset of highly interconnected proteins in an ER-mitochondria organization network, which were consistently down-regulated with aging. These decreased proteins, including VDAC1, SAMM50, MTX1 and MIC60, were considered as potential contributors to the age-related MAM dysfunction. This study highlights the perturbation in MAM integrity during the striated muscle aging process, and provides a framework for understanding aging biology from the perspective of organelle interactions. |
| first_indexed | 2024-04-12T22:32:11Z |
| format | Article |
| id | doaj.art-da979a1d39b84df2891f86d0fe5c0d6e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T22:32:11Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-da979a1d39b84df2891f86d0fe5c0d6e2022-12-22T03:13:56ZengNature Publishing GroupCell Death and Disease2041-48892022-04-0113411510.1038/s41419-022-04746-4Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscleXue Lu0Yingchao Gong1Wanyu Hu2Yankai Mao3Ting Wang4Zeyu Sun5Xiaoling Su6Guosheng Fu7Yanpeng Wang8Dongwu Lai9Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineKey Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineHangzhou Medical CollegeState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityKey Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Gynecology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College)Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract Aging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using quantitative morphological analysis, we showed that the mitochondria-endoplasmic reticulum contacts (MERCs) were reduced by half over the lifespan with an early onset of accelerated thickening in the clefts. The ultrastructural changes were further validated by proteomic profiling of the MAM fractions. A combination of subcellular fractionation and quantitative mass spectrometry identified 1306 MAM-enriched proteins in both heart and skeletal muscle, with a catalog of proteins dysregulated with aging. Functional mapping of the MAM proteome suggested several aging signatures to be closely associated with the ER-mitochondria crosstalk, including local metabolic rewiring, calcium homeostasis imbalance, and impaired organelle dynamics and autophagy. Moreover, we identified a subset of highly interconnected proteins in an ER-mitochondria organization network, which were consistently down-regulated with aging. These decreased proteins, including VDAC1, SAMM50, MTX1 and MIC60, were considered as potential contributors to the age-related MAM dysfunction. This study highlights the perturbation in MAM integrity during the striated muscle aging process, and provides a framework for understanding aging biology from the perspective of organelle interactions.https://doi.org/10.1038/s41419-022-04746-4 |
| spellingShingle | Xue Lu Yingchao Gong Wanyu Hu Yankai Mao Ting Wang Zeyu Sun Xiaoling Su Guosheng Fu Yanpeng Wang Dongwu Lai Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle Cell Death and Disease |
| title | Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| title_full | Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| title_fullStr | Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| title_full_unstemmed | Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| title_short | Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| title_sort | ultrastructural and proteomic profiling of mitochondria associated endoplasmic reticulum membranes reveal aging signatures in striated muscle |
| url | https://doi.org/10.1038/s41419-022-04746-4 |
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