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

doi:10.1038/s41467-018-08276-6

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

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English
Article number	329
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08276-6
State	Published - 1 Dec 2019
Externally published	Yes

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).

Access to Document

10.1038/s41467-018-08276-6

Cite this

Ferreira, J. C. B., Campos, J. C., Qvit, N., Qi, X., Bozi, L. H. M., Bechara, L. R. G., Lima, V. M., Queliconi, B. B., Disatnik, M. H., Dourado, P. M. M., Kowaltowski, A. J., & Mochly-Rosen, D. (2019). A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats. Nature Communications, 10(1), Article 329. https://doi.org/10.1038/s41467-018-08276-6

@article{8e4c92f140dc4f23ad4a99a2f5d4d706,

title = "A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats",

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.",

author = "Ferreira, {Julio C.B.} and Campos, {Juliane C.} and Nir Qvit and Xin Qi and Bozi, {Luiz H.M.} and Bechara, {Luiz R.G.} and Lima, {Vanessa M.} and Queliconi, {Bruno B.} and Disatnik, {Marie Helene} and Dourado, {Paulo M.M.} and Kowaltowski, {Alicia J.} and Daria Mochly-Rosen",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-08276-6",

language = "אנגלית",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats

AU - Ferreira, Julio C.B.

AU - Campos, Juliane C.

AU - Qvit, Nir

AU - Qi, Xin

AU - Bozi, Luiz H.M.

AU - Bechara, Luiz R.G.

AU - Lima, Vanessa M.

AU - Queliconi, Bruno B.

AU - Disatnik, Marie Helene

AU - Dourado, Paulo M.M.

AU - Kowaltowski, Alicia J.

AU - Mochly-Rosen, Daria

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060148784&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-08276-6

DO - 10.1038/s41467-018-08276-6

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 30659190

AN - SCOPUS:85060148784

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 329

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this