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
  • 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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