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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Ferreira, Julio C. B. [1, 2] ; Campos, Juliane C. [2] ; Qvit, Nir [1] ; Qi, Xin [1, 3] ; Bozi, Luiz H. M. [2] ; Bechara, Luiz R. G. [2] ; Lima, Vanessa M. [2] ; Queliconi, Bruno B. [4] ; Disatnik, Marie-Helene [1] ; Dourado, Paulo M. M. [5] ; Kowaltowski, Alicia J. [4] ; Mochly-Rosen, Daria [1]
Total Authors: 12
Affiliation:
[1] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, BR-05508000 Sao Paulo, SP - Brazil
[3] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 - USA
[4] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil
[5] Univ Sao Paulo, Inst Heart, BR-05403010 Sao Paulo, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: NATURE COMMUNICATIONS; v. 10, JAN 18 2019.
Web of Science Citations: 4
Abstract

We previously demonstrated that beta II protein kinase C (beta IIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that beta IIPKC 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. beta IIPKC siRNA or a beta IIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-beta IIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAM beta A, a rationally-designed peptide that selectively antagonizes Mfn1-ss IIPKC association. SAM beta A treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAM beta A treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAM beta A may be a potential treatment for patients with heart failure. (AU)

FAPESP's process: 10/00028-4 - Characterization of mitochondrial fusion and fission in heart failure: effects of exercise training
Grantee:Patricia Chakur Brum
Support Opportunities: Regular Research Grants
FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
Grantee:Carlos Eduardo Negrão
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/16694-2 - Impact of 4-hydroxinonenal on DICER regulation: a translational approach
Grantee:Julio Cesar Batista Ferreira
Support Opportunities: Regular Research Grants
FAPESP's process: 17/11142-1 - Mitochondrial formyl peptides as signaling molecules: new perspective in the treatment of cardiac ischemia/reperfusion injury.
Grantee:Luiz Roberto Grassmann Bechara
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development
Grantee:Julio Cesar Batista Ferreira
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
Grantee:Alicia Juliana Kowaltowski
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/16540-5 - Exercise, lifespan and healthspan: a molecular and longitudinal approach to study their interactions
Grantee:Juliane Cruz Campos
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 09/12349-2 - Characterization of mitochondrial function and dynamics in cardiac dysfunction-induced myocardial infarction in rats
Grantee:Juliane Cruz Campos
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 16/01633-5 - BETA2-ADRENOCEPTOR ACTIVATION COUNTERACTS SKELETAL MUSCLE WEAKNESS/WASTING: ROLE OF AUTOPHAGY
Grantee:Juliane Cruz Campos
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 16/09611-0 - Doxorubicin-induced cardiotoxicity: role of mitochondrial retrograde signaling activated by protein imbalance
Grantee:Luiz Henrique Marchesi Bozi
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 15/20783-5 - Protein quality control in dysfunctional/atrophic skeletal muscle: role of b2-adrenoceptor
Grantee:Julio Cesar Batista Ferreira
Support Opportunities: Regular Research Grants