A Selective Inhibitor of Mitofusin 1-βIIPKC Association Improves Heart Failure Outcome in Rats

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 20

PMID 30659190

Citations 52

Authors

Julio C B Ferreira

Juliane C Campos

Nir Qvit

Xin Qi

Luiz H M Bozi

Luiz R G Bechara

Vanessa M Lima

Bruno B Queliconi

Marie-Helene Disatnik

Paulo M M Dourado

Alicia J Kowaltowski

Daria Mochly-Rosen

Affiliations

Soon will be listed here.

Abstract

We previously demonstrated that beta II protein kinase C (βIIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure. βIIPKC siRNA or a βIIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-βIIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAMβA, a rationally-designed peptide that selectively antagonizes Mfn1-βIIPKC association. SAMβA treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAMβA treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAMβA may be a potential treatment for patients with heart failure.

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