A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats
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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 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.
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Inhibition of MFN1 GTPase activity leads to mitochondrial fragmentation and dysfunction that contribute to heart failure progression in mice.
“Accordingly, inhibition of MFN1 GTPase activity leads to mitochondrial fragmentation and dysfunction that contribute to heart failure progression in mice [191].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [191]
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- Authors
- Ferreira, J. C. B., Campos, J. C., Qvit, N., Qi, X., Bozi, L. H. M., Bechara, L. R. G., Lima, V. M., Queliconi, B. B., Disatnik, M.-H., Dourado, P. M. M., Kowaltowski, A. J., & Mochly-Rosen, D.
- Affiliations
- Universidade de São Paulo (BR)
- Stanford Medicine (US)
- Corresponding author
- Ferreira, Julio C. B.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-01-18
- Volume
- 10
- Issue
- 1
- Pages
- 329-329
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6338754
- OpenAlex
- W2909282279
- Cited by
- 99
- References
- 55
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 15 · 2023: 14 · 2022: 26 · 2021: 12 · 2020: 14 · 2019: 5
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-04-03)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (10/51906-1, 12/05765-2, 2017/11142-1, 2015/, 15/20783-5, 2017/16540‐5, 2015/228145, 407306/2013-7, 17/16694-2, 2010/51906, 470880/2012-0, 2016/09611-0, 2016/01633-5, Code 001)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (2017/16694-2, 2015/20783-5, (Code 001), 2012/05765-2, 2017/16540-5, 2017/11142-1, 407306/2013-7, 470880/2012-0)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (2015-4, 470880/2012-0, 2017/11142-1, 2015/22814-5, 407306/2013-7, 2012-0, 2017/16694-2, 2017/16540-5, 2012/05765-2, 2015/20783-5)
- National Heart, Lung, and Blood Institute (R01HL052141)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- mitofusin 1, heart failure, mitochondrial fragmentation, peptide inhibitors, mitochondrial morphology, cardiac contractility, cardiomyocyte death
- MeSH terms
- Animals, Heart Failure, Male, Membrane Proteins, Myocardial Contraction, Myocardial Infarction, Peptides, Phosphorylation, Rats, Wistar, GTP Phosphohydrolases, Mitochondrial Proteins, Myocytes, Cardiac, RNA, Small Interfering, Mitochondrial Membranes, Gene Knockout Techniques, Protein Kinase C beta
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