Back to Search
Start Over
A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats.
- Source :
-
Nature communications [Nat Commun] 2019 Jan 18; Vol. 10 (1), pp. 329. Date of Electronic Publication: 2019 Jan 18. - Publication Year :
- 2019
-
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.
- Subjects :
- Animals
GTP Phosphohydrolases metabolism
Gene Knockout Techniques
Heart Failure metabolism
Male
Mitochondrial Membranes metabolism
Myocardial Contraction
Myocardial Infarction metabolism
Myocardial Infarction pathology
Myocytes, Cardiac drug effects
Phosphorylation
RNA, Small Interfering
Rats, Wistar
Heart Failure drug therapy
Membrane Proteins antagonists & inhibitors
Mitochondrial Proteins antagonists & inhibitors
Peptides pharmacology
Protein Kinase C beta antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30659190
- Full Text :
- https://doi.org/10.1038/s41467-018-08276-6