Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence

Akiyuki Nishimura, Tsukasa Shimauchi, Tomohiro Tanaka, Kakeru Shimoda, Takashi Toyama, Naoyuki Kitajima, Tatsuya Ishikawa, Naoya Shindo, Takuro Numaga-Tomita, Satoshi Yasuda, Yoji Sato, Koichiro Kuwahara, Yoshito Kumagai, Takaaki Akaike, Tomomi Ide, Akio Ojida, Yasuo Mori, Motohiro Nishida

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereaat5185
JournalScience Signaling
Volume11
Issue number556
DOIs
Publication statusPublished - 2018 Nov 13

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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