biostudies-literatureFerreira JCBNHLBI NIH HHS329https://www.ebi.ac.uk/biostudies/studies/S-EPMC6338754biostudies-literatureUnknown10(1)We previously demonstrated that beta II protein kinase C (?IIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that ?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. ?IIPKC siRNA or a ?IIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-?IIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAM?A, a rationally-designed peptide that selectively antagonizes Mfn1-?IIPKC association. SAM?A treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAM?A treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAM?A may be a potential treatment for patients with heart failure.Nature communicationsA selective inhibitor of mitofusin 1-?IIPKC association improves heart failure outcome in rats.PMC6338754R01 HL052141Disatnik MHFerreira JCBBechara LRGLima VMDourado PMMCampos JCQvit NQi XBozi LHMKowaltowski AJQueliconi BBMochly-Rosen DfalseA selective inhibitor of mitofusin 1-?IIPKC association improves heart failure outcome in rats.We previously demonstrated that beta II protein kinase C (?IIPKC) activity is elevated in failing hearts and contributes to this pathology. Here we report that ?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. ?IIPKC siRNA or a ?IIPKC inhibitor mitigates mitochondrial fragmentation and cell death. We confirm that Mfn1-?IIPKC interaction alone is critical in inhibiting mitochondrial function and cardiac myocyte viability using SAM?A, a rationally-designed peptide that selectively antagonizes Mfn1-?IIPKC association. SAM?A treatment protects cultured neonatal and adult cardiac myocytes, but not Mfn1 knockout cells, from stress-induced death. Importantly, SAM?A treatment re-establishes mitochondrial morphology and function and improves cardiac contractility in rats with heart failure, suggesting that SAM?A may be a potential treatment for patients with heart failure.2019-01-01T00:00:00Z2019 Jan2021-02-19T08:14:09Z2019-03-26T22:39:04ZS-EPMC63387543065919010.1038/s41467-018-08276-6