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-βIIPKC association improves heart failure outcome in rats. Nat Commun 10:329.|
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.
Labels: MiParea: Respiration Pathology: Cardiovascular
Organism: Rat Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: NS HRR: Oxygraph-2k