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

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.