Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence
| Autor: | Kakeru Shimoda, Yasuo Mori, Takuro Numaga-Tomita, Takashi Toyama, Tatsuya Ishikawa, Koichiro Kuwahara, Satoshi Yasuda, Tomohiro Tanaka, Takaaki Akaike, Tomomi Ide, Naoya Shindo, Akiyuki Nishimura, Naoyuki Kitajima, Motohiro Nishida, Yoji Sato, Akio Ojida, Yoshito Kumagai, Tsukasa Shimauchi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Senescence Dynamins Male endocrine system Cardiac Catheterization Dihydropyridines Filamins Myocardial Infarction macromolecular substances Plasma protein binding GTPase Mitochondrion Filamin Biochemistry Mitochondrial Dynamics Rats Sprague-Dawley 03 medical and health sciences Mice Animals Humans Molecular Biology Actin Cellular Senescence Chemistry Myocardium Cell Biology Actin cytoskeleton Calcium Channel Blockers Cell Hypoxia Cell biology Rats Mice Inbred C57BL 030104 developmental biology Echocardiography Mutation Calcium Guanine nucleotide exchange factor Guanosine Triphosphate Reactive Oxygen Species HeLa Cells Protein Binding |
| Zdroj: | Science signaling. 11(556) |
| ISSN: | 1937-9145 |
| Popis: | Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission–accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission–associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding–dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1–filamin A interaction by cilnidipine suppressed mitochondrial hyperfission–associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development. |
| Databáze: | OpenAIRE |
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