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

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 p...

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Veröffentlicht in:Nature communications 2019-01, Vol.10 (1), p.329-329, Article 329
Hauptverfasser: Ferreira, Julio C. B., Campos, Juliane C., Qvit, Nir, Qi, Xin, Bozi, Luiz H. M., Bechara, Luiz R. G., Lima, Vanessa M., Queliconi, Bruno B., Disatnik, Marie-Helene, Dourado, Paulo M. M., Kowaltowski, Alicia J., Mochly-Rosen, Daria
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Sprache:eng
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Zusammenfassung: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. Beta II protein kinase C (βIIPKC) activation contributes to heart failure. Here the authors show, in a rat model of myocardial infarction, that heart failure outcome can be improved by selectively inhibiting the interaction between βIIPKC and its downstream mitochondrial target Mitofusin-1, and that this strategy is superior to global βIIPKC inhibition.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-08276-6