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 journalArticle

4 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 - Nov 13 2018

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Filamins
Dynamins
Actins
Mitochondrial Dynamics
Proteins
Myocardial Infarction
Mitochondria
Actin Cytoskeleton
Dynamin I
Heart Failure
Guanine Nucleotide Exchange Factors
Microfilament Proteins
Hypoxia
GTP Phosphohydrolases
Cardiac Myocytes
Rats
Agglomeration
Pharmacology

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. / Nishimura, Akiyuki; Shimauchi, Tsukasa; Tanaka, Tomohiro; Shimoda, Kakeru; Toyama, Takashi; Kitajima, Naoyuki; Ishikawa, Tatsuya; Shindo, Naoya; Numaga-Tomita, Takuro; Yasuda, Satoshi; Sato, Yoji; Kuwahara, Koichiro; Kumagai, Yoshito; Akaike, Takaaki; Ide, Tomomi; Ojida, Akio; Mori, Yasuo; Nishida, Motohiro.

In: Science Signaling, Vol. 11, No. 556, eaat5185, 13.11.2018.

Research output: Contribution to journalArticle

Nishimura, A, Shimauchi, T, Tanaka, T, Shimoda, K, Toyama, T, Kitajima, N, Ishikawa, T, Shindo, N, Numaga-Tomita, T, Yasuda, S, Sato, Y, Kuwahara, K, Kumagai, Y, Akaike, T, Ide, T, Ojida, A, Mori, Y & Nishida, M 2018, 'Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence' Science Signaling, vol. 11, no. 556, eaat5185. https://doi.org/10.1126/scisignal.aat5185
Nishimura, Akiyuki ; Shimauchi, Tsukasa ; Tanaka, Tomohiro ; Shimoda, Kakeru ; Toyama, Takashi ; Kitajima, Naoyuki ; Ishikawa, Tatsuya ; Shindo, Naoya ; Numaga-Tomita, Takuro ; Yasuda, Satoshi ; Sato, Yoji ; Kuwahara, Koichiro ; Kumagai, Yoshito ; Akaike, Takaaki ; Ide, Tomomi ; Ojida, Akio ; Mori, Yasuo ; Nishida, Motohiro. / Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. In: Science Signaling. 2018 ; Vol. 11, No. 556.
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