CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation
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Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca 2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.
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DRP1 promotes PTPC opening in response to chronic β adrenergic receptor stimulation via mechanism relying on DRP1 phosphorylation by CaMKII.
“(2) DRP1, which appears to promote PTPC opening in response to chronic β adrenergic receptor stimulation, via a mechanism that relies on DRP1 phosphorylation by calcium/calmodulin dependent protein kinase II (CAMK2G; best known as CaMKII) [415]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [415]
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- Authors
- Xu, S., Wang, P., Zhang, H., Gong, G., Gutierrez Cortes, N., Zhu, W., Yoon, Y., Tian, R., & Wang, W.
- Affiliations
- Army Medical University (CN)
- University of Washington (US)
- Nantong University (CN)
- Augusta University (US)
- Corresponding author
- Xu, Shangcheng
- Wang, Wang
- ORCID
- Venue
- Nature Communications
- Published
- 2016-10-14
- Volume
- 7
- Issue
- 1
- Pages
- 13189-13189
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5067512
- OpenAlex
- W2531386549
- Cited by
- 218
- References
- 52
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 25 · 2023: 22 · 2022: 25 · 2021: 30 · 2020: 26 · 2019: 16 · 2018: 21 · 2017: 14
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association (HL114760, HL110349, 10SDG3450009)
- National Key Research and Development Program of China
- National Heart, Lung, and Blood Institute (R01HL110349, R01HL114760)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- mitochondrial permeability transition pore, CaMKII, Drp1 phosphorylation, Drp1, beta-adrenergic stimulation, isoproterenol, cardiac hypertrophy, mitochondrial fission, mitochondrial dysfunction, cardiomyocyte death, heart failure, calcium/calmodulin signaling
- MeSH terms
- Mitochondrial Permeability Transition Pore, Adrenergic beta-Agonists, Animals, Cell Line, Cells, Cultured, Female, Isoproterenol, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Phosphorylation, Receptors, Adrenergic, beta, Rats, Sprague-Dawley, Mice, Knockout, Myocytes, Cardiac, Mitochondrial Membrane Transport Proteins, Dynamins, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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