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A selective inhibitor of mitofusin 1-?IIPKC association improves heart failure outcome in rats.


ABSTRACT: 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.

SUBMITTER: Ferreira JCB 

PROVIDER: S-EPMC6338754 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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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 dea  ...[more]

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