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

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 and Daria Mochly-Rosen ()
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Julio C. B. Ferreira: University of Sao Paulo
Juliane C. Campos: University of Sao Paulo
Nir Qvit: Stanford University School of Medicine
Xin Qi: Stanford University School of Medicine
Luiz H. M. Bozi: University of Sao Paulo
Luiz R. G. Bechara: University of Sao Paulo
Vanessa M. Lima: University of Sao Paulo
Bruno B. Queliconi: Universidade de Sao Paulo
Marie-Helene Disatnik: Stanford University School of Medicine
Paulo M. M. Dourado: University of Sao Paulo
Alicia J. Kowaltowski: Universidade de Sao Paulo
Daria Mochly-Rosen: Stanford University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08276-6

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