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

Akiyuki Nishimura1,2,3,4, Tsukasa Shimauchi1,2,5, Tomohiro Tanaka1,2

  • 1National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Aichi 444-8787, Japan.

Science Signaling
|November 15, 2018
PubMed

Insights

Filamin A links mitochondria and actin, driving heart damage after myocardial infarction (MI). Blocking this interaction with cilnidipine may protect the heart and prevent heart failure.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Dynamics
  • Cellular Senescence

Background:

  • Defective mitochondrial dynamics, involving interactions between mitochondria and the actin cytoskeleton, are critical in cardiac dysfunction post-myocardial infarction (MI).
  • Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and is activated via actin interactions, contributing to cardiac fragility.

Purpose of the Study:

  • To investigate the role of actin-binding protein filamin A in mediating mitochondrial fission-associated myocardial senescence after MI.
  • To explore the therapeutic potential of targeting the Drp1-filamin A interaction in treating heart failure post-MI.

Main Methods:

  • Investigated filamin A and Drp1 colocalization in peri-infarct regions of mouse hearts post-MI.
  • Examined the effect of hypoxic stress on filamin A-Drp1 interaction and Drp1 activity in rat cardiomyocytes.
  • Utilized a filamin A mutant to assess its impact on mitochondrial fission.
  • Evaluated the efficacy of cilnidipine in perturbing the Drp1-filamin A interaction and mitigating cardiac damage.

Main Results:

  • Filamin A colocalized with Drp1 around mitochondria in peri-infarct zones, correlating with mitochondrial hyperfission and myocardial senescence.
  • Hypoxic stress increased filamin A-Drp1 interaction and Drp1 activity in a manner dependent on actin binding.
  • A filamin A mutant potentiating actin aggregation induced mitochondrial hyperfission.
  • Cilnidipine treatment suppressed mitochondrial hyperfission, myocardial senescence, and heart failure post-MI.

Conclusions:

  • The Drp1-filamin A interaction with the actin cytoskeleton exacerbates cardiac fragility and senescence following myocardial infarction.
  • Targeting the Drp1-filamin A interaction, for example, with cilnidipine, offers a promising therapeutic strategy for heart failure post-MI.
  • This study provides a basis for developing novel Drp1 inhibitors for cardiovascular diseases.

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