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.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Health Grant HL52141 to D.M.-R.; Fundação de Amparo à Pesquisa do Estado de São Paulo—Brasil (FAPESP #2009/12349-2, #2010/00028-4, #2010/51906-1, #2012/05765-2, #2015/20783-5, #2016/01633-5, #2015/22814-5, #2016/09611-0, #2017/16694-2, #2017/11142-1, and #2017/16540-5 to J. C.B.F.), Conselho Nacional de Pesquisa e Desenvolvimento (CNPq)—Brasil [#303281/ 2015-4, #470880/2012-0, and #407306/2013-7 to J.C.B.F.], Coordenação de Aperfeiçoa-mento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001; and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Pro-cessos Redox em Biomedicina. We thank Camille C. Caldeira-da-Silva for technical assistance.
© 2019, The Author(s).