Ferreira 2019 Nat Commun
| Ferreira JCB, Campos JC, Qvit N, Qi X, Bozi LHM, Bechara LRG, Lima VM, Queliconi BB, Disatnik MH, Dourado PMM, Kowaltowski AJ, Mochly-Rosen D (2019) A selective inhibitor of mitofusin 1-Ī²IIPKC association improves heart failure outcome in rats. Nat Commun 10:329. |
Ferreira JCB, Campos JC, Qvit N, Qi X, Bozi LHM, Bechara LRG, Lima VM, Queliconi BB, Disatnik MH, Dourado PMM, Kowaltowski AJ, Mochly-Rosen D (2019) Nat Commun
Abstract: We previously demonstrated that beta II protein kinase C (Ī²IIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that Ī²IIPKC 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. Ī²IIPKC siRNA or a Ī²IIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-Ī²IIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAMĪ²A, a rationally-designed peptide that selectively antagonizes Mfn1-Ī²IIPKC association. SAMĪ²A treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAMĪ²A treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAMĪ²A may be a potential treatment for patients with heart failure.
ā¢ Bioblast editor: Plangger M ā¢ O2k-Network Lab: BR Sao Paulo Ferreira JCB, BR Sao Paulo Kowaltowski AJ
Labels: MiParea: Respiration
Pathology: Cardiovascular
Organism: Rat Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET
Pathway: NS
HRR: Oxygraph-2k
2019-01
