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

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

The MyMOMA domain of MYO19 encodes for distinct Miro-dependent and Miro-independent mechanisms of interaction with mitochondrial membranes

“…Filamins are actin crosslinking proteins involved in actin-based cellular activities via interactions with a large number of other protein partners [Nakamura et al 2011]. It was recently reported that DRP1, a component of the mitochondrial fission machinery, and filamin A interact in response to hypoxic stress [Nishimura et al 2018]. Palladin is an actin crosslinking protein originally characterized in the stress fibers of fibroblasts and cardiac myocytes [Parast and Otey 2000].…”

Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway

“…In fact, many studies have reported the role of mitochondrial fission in cardiac physiology and pathophysiology (Adaniya et al 2019). For example, in myocardial senescence, DRP1mediated mitochondrial hyperfusion promotes cardiomyocyte dysfunction by inducing oxidative stress (Nishimura et al 2018), and in myocardial ischemia reperfusion injury, the inhibition of DRP1-related mitochondrial fission via mi-RNA-140 promotes cardiomyocyte survival by repressing mitochondria-related cardiomyocyte death (Yang et al 2019). Moreover, in postinfarction cardiac injury, Sirt3mediated cardioprotection is dependent on the inhibition of mitochondrial fission through the AMPK-DRP1 pathway (Liu et al 2019).…”

SFRP2 modulates non‑small cell lung cancer A549�cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways

“…impaired mitochondrial function inhibited cancer cell migration, invasion and survival, and increased cancer cell apoptosis (14). dynamin-related protein 1 (drp1)-associated mitochondrial fission serves an important role in the regulation of mitochondrial function (15)(16)(17)(18)(19). additionally, a recent study determined that mitochondrial fission was involved in the regulation of a549 nSclc cell survival and migration (20).…”