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-ฮฒIIPKC 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 (ฮฒIIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that ฮฒIIPKC 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. ฮฒIIPKC siRNA or a ฮฒIIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-ฮฒIIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAMฮฒA, a rationally-designed peptide that selectively antagonizes Mfn1-ฮฒIIPKC association. SAMฮฒA treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAMฮฒA treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAMฮฒA may be a potential treatment for patients with heart failure.
โข Bioblast editor: Plangger M โข 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: N, NS
HRR: Oxygraph-2k, O2k-Fluorometer
Labels, 2019-01, Amplex UltraRed
