2. Academic Validation
  3. A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats

A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats

  • Nat Commun. 2019 Jan 18;10(1):329. doi: 10.1038/s41467-018-08276-6.
Julio C B Ferreira 1 2,  Juliane C Campos 3,  Nir Qvit 4,  Xin Qi 4 5,  Luiz H M Bozi 3,  Luiz R G Bechara 3,  Vanessa M Lima 3,  Bruno B Queliconi 6,  Marie-Helene Disatnik 4,  Paulo M M Dourado 7,  Alicia J Kowaltowski 6,  Daria Mochly-Rosen 8
Affiliations

Affiliations

  • 1 Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000, SP, Brazil. [email protected].
  • 2 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, 94305-5174, CA, USA. [email protected].
  • 3 Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000, SP, Brazil.
  • 4 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, 94305-5174, CA, USA.
  • 5 Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, 44106, OH, USA.
  • 6 Departamento de Bioquímica, Instituto de Química, Universidade de Sao Paulo, Sao Paulo, 05508-000, SP, Brazil.
  • 7 Heart Institute, University of Sao Paulo, Sao Paulo, 05403-010, SP, Brazil.
  • 8 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, 94305-5174, CA, USA. [email protected].
PMID: 30659190 DOI: 10.1038/s41467-018-08276-6
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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