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

Author(s):Show less -

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]

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

• 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 type: Regular Research Grants
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support type: 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 type: 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 type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development
• Grantee: Julio Cesar Batista Ferreira
• Support type: 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 type: 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 type: Scholarships in Brazil - Post-Doctorate
• 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 type: 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 type: 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 type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/20783-5 - Protein quality control in dysfunctional/atrophic skeletal muscle: role of b2-adrenoceptor
• Grantee: Julio Cesar Batista Ferreira
• Support type: Regular Research Grants