Research ArticleCardiovascular Biology

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

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Science Signaling  13 Nov 2018:
Vol. 11, Issue 556, eaat5185
DOI: 10.1126/scisignal.aat5185

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Breaking mitochondria and hearts

Blocking the excessive mitochondrial fission mediated by Drp1 that occurs after myocardial infarction prevents the development of cardiac dysfunction. Nishimura et al. (see also the Focus by Boyer and Eguchi) sought to understand why Drp1 activity is increased after myocardial infarction, an unfortunately common cause of mortality and morbidity in developed nations. They found that the cytoskeletal regulator filamin increased the mitochondrial fission activity of Drp1, an effect that led to cardiomyocyte senescence. The association of filamin with Drp1, which was actin dependent, was increased in infarcted heart tissue from mice. Screening identified the antihypertensive drug cilnidipine, initially characterized as a Ca2+ channel blocker, as a small-molecule inhibitor of the interaction between filamin and Drp1. Administering cilnidipine to mice after the induction of myocardial infarction reduced mitochondrial fission, cardiomyocyte senescence, and myocardial dysfunction independently of the drug’s effects on Ca2+ channels. These results identify a mechanism that increases Drp1 activity after myocardial infarction and a drug that could be repurposed to treat this all-too-common event.

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.

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