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, Daria Mochly-Rosen

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60 Scopus citations


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.

Original languageEnglish
Article number329
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2019
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health Grant HL52141 to D.M.-R.; Fundação de Amparo à Pesquisa do Estado de São Paulo—Brasil (FAPESP #2009/12349-2, #2010/00028-4, #2010/51906-1, #2012/05765-2, #2015/20783-5, #2016/01633-5, #2015/22814-5, #2016/09611-0, #2017/16694-2, #2017/11142-1, and #2017/16540-5 to J. C.B.F.), Conselho Nacional de Pesquisa e Desenvolvimento (CNPq)—Brasil [#303281/ 2015-4, #470880/2012-0, and #407306/2013-7 to J.C.B.F.], Coordenação de Aperfeiçoa-mento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001; and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Pro-cessos Redox em Biomedicina. We thank Camille C. Caldeira-da-Silva for technical assistance.

Publisher Copyright:
© 2019, The Author(s).


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