LncRNA LOC105378097 inhibits cardiac mitophagy in natural ageing mice
Xin Liu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
With equal contribution to this work.
Search for more papers by this authorXue Bai
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
With equal contribution to this work.
Search for more papers by this authorHeng Liu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
With equal contribution to this work.
Search for more papers by this authorYang Hong
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHao Cui
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorLei Wang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorWanqing Xu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorLimin Zhao
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorXiaohan Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHuimin Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorXia Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHui Chen
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorZiyu Meng
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHan Lou
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHenghui Xu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorYuan Lin
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorZhimin Du
Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
Search for more papers by this authorPhilipp Kopylov
Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
Search for more papers by this authorCorresponding Author
Baofeng Yang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne, Melbourne, Australia
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
Correspondence
Yong Zhang and Baofeng Yang, Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yong Zhang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China
Correspondence
Yong Zhang and Baofeng Yang, Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Email: [email protected]; [email protected]
Search for more papers by this authorXin Liu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
With equal contribution to this work.
Search for more papers by this authorXue Bai
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
With equal contribution to this work.
Search for more papers by this authorHeng Liu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
With equal contribution to this work.
Search for more papers by this authorYang Hong
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHao Cui
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorLei Wang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorWanqing Xu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorLimin Zhao
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorXiaohan Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHuimin Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorXia Li
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHui Chen
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorZiyu Meng
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHan Lou
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorHenghui Xu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorYuan Lin
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Search for more papers by this authorZhimin Du
Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
Search for more papers by this authorPhilipp Kopylov
Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
Search for more papers by this authorCorresponding Author
Baofeng Yang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne, Melbourne, Australia
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
Correspondence
Yong Zhang and Baofeng Yang, Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yong Zhang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, China
Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China
Correspondence
Yong Zhang and Baofeng Yang, Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Email: [email protected]; [email protected]
Search for more papers by this authorAbstract
Background
The development of heart ageing is the main cause of chronic disability, disease and death in the elderly. Ample evidence has established a pivotal role for significantly reduced mitophagy in the ageing heart. However, the underlying mechanisms of mitophagy deficiency in ageing heart are little known. The present study aimed to explore the underlying mechanisms of lncRNA LOC105378097 (Senescence-Mitophagy Associated LncRNA, lncR-SMAL) actions on mitophagy in the setting of heart ageing.
Methods
The expression of lncR-SMAL was measured in serum from different ages of human and heart from different ages of mice through a quantitative real-time polymerase chain reaction. The effects of lncR-SMAL on heart function of mice were assessed by echocardiography and pressure-volume measurements system. Cardiac senescence was evaluated by hematoxylin-eosin staining, senescence-associated β-galactosidase staining, flow cytometry and western blot analysis of expression of ageing related markes p53 and p21. Cardiomyocyte mitophagy was assessed by western blot, mRFP-GFP-LC3 adenovirus particles transfection and mito-Keima staining. Interaction between lncR-SMAL and Parkin was validated through molecular docking, RNA immunoprecipitation (RIP) and RNA pull-down assay. Ubiquitination assay was performed to explore the molecular mechanism of Parkin inhibition. The effects of lncR-SMAL on mitochondrial function were investigated through electron microscopic examination, JC-1 staining and oxygen consumption rates analysis.
Results
The heart-enriched lncR-SMAL reached the expression crest in the serum of human at an age of 60. Exogenously overexpression of lncRNA SMAL deteriorated cardiac function exactly as natural ageing and inhibited the associated cardiomyocytes mitophagy by depressing Parkin protein level. Improved heart ageing and mitophagy caused by Parkin overexpression were reversed by lncR-SMAL in mice. In contrast, the loss of lncR-SMAL in AC16 cells induced the upregulation of Parkin protein and ameliorated mitophagy and mitochondrial dysfunction, resulting in alleviated cardiac senescence. Besides, we found the interaction between lncR-SMAL and Parkin protein through computational docking analysis, pull-down and RIP assay. This would contribute to the promotive effect of lncR-SMAL on Parkin ubiquitination and decrease Parkin protein stability.
Conclusions
The present study for the first time demonstrates a heart-enriched lncRNA, SMAL, that inhibits the mitophagy of cardiomyocytes via the downregulation of Parkin protein, which further contributes to heart ageing and cardiac dysfunction in natural ageing mice.
CONFLICT OF INTERESTS
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Supporting Information
| Filename | Description |
|---|---|
| ctm2908-sup-0001-SuppMat.docx1.6 MB | Figure S1 LncR-SMAL is highly specifically expressed in senescent cardiomyocytes Figure S2 Effects of lncR-SMAL on cardiac systolic function and senescence Figure S3 Homology sequence analysis of lncR-SMAL between human and mouse Figure S4 Overexpression of lncR-SMAL inhibits autophagy and causes senescence Figure S5 Interaction between lncR-SMAL and Parkin protein in senescent AC16 cells Figure S6 LncR-SMAL targets Parkin to regulate cell senescence Figure S7 Knockout of Parkin cancels the regulation of lncR-SMAL on autophagy and senescence Figure S8 BAFA1 blocks the beneficial effects of si-SMAL on mitophagy and senescence Figure S9 Knockdown of lncR-SMAL improves mitophagy Table S1. Clinical information of patient blood samples |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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