Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission‐ VDAC 1‐ HK 2‐ mPTP ‐mitophagy axis
Open accessAbstract
Abstract The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury ( IRI ) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells ( CMEC ) in melatonin‐treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP‐activated protein kinase α ( AMPK α) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission, which subsequently induced voltage‐dependent anion channel 1 ( VDAC 1) oligomerization, hexokinase 2 ( HK 2) liberation, mitochondrial permeability transition pore ( mPTP ) opening, PINK 1/Parkin upregulation, and ultimately mitophagy‐mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPK α, followed by p‐Drp1 S616 downregulation and p‐Drp1 S37 upregulation, which blunted Drp1‐dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC 1‐ HK 2 interaction that prevented mPTP opening and PINK 1/Parkin activation, eventually blocking mitophagy‐mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI . The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission‐ VDAC 1‐ HK 2‐ mPTP ‐mitophagy axis via activation of AMPKα.
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Melatonin treatment reveals a protective role in cardiac microvasculature under I/R injury by activating AMPK.
“Melatonin treatment reveals a protective role in cardiac microvasculature under I/R injury by activating AMPK [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
Prevention of mitochondrial fission restored the interaction between voltage-dependent anion channel 1 and hexokinase 2, stopped mitochondrial permeability transition pore opening, and PINK1-PARKIN activation, ultimately blunting cell death.
“The prevention of mitochondrial fission further restored the interaction between voltage-dependent anion channel 1 and hexokinase 2, stopped mitochondrial permeability transition pore opening, and PINK1–PARKIN activation, ultimately blunting cell death [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
Melatonin significantly decreased myocardial infarction, improved cardiac function, normalized blood flow, and lowered microcirculation perfusion impairment.
“Melatonin significantly decreased myocadiac infarction, improved cardiac function, normalized blood flow, and lowered microcirculation perfusion impairment [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
I/R triggered a DRP1-dependent mitochondrial fragmentation, which subsequently led to oligomerization of voltage-dependent anion channel 1, liberation of hexokinase 2, opening of mitochondrial permeability transition pore, upregulation of PINK1-PARKIN signaling, and eventual mitophagy-mediated cell death.
“In vitro mechanism studies showed that I/R triggered a DRP1-dependent mitochondrial fragmentation, which subsequently led to oligomerization of voltage-dependent anion channel 1, liberation of hexokinase 2, opening of mitochondrial permeability transition pore, upregulation of PINK1–PARKIN signaling, and eventual mitophagy-mediated cell death [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
Administration of melatonin restored the endothelial barrier, promoted eNOS expression, decreased inflammatory cell infiltration, and lowered endothelial damage in cardiac microcirculation endothelial cells.
“Histological analysis revealed that administration of melatonin restored the endothelial barrier, promoted eNOS expression, decreased inflammatory cell infiltration, and lowered endothelial damage in cardiac microcirculation endothelial cells [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
Melatonin promoted cell survival via AMPKα activation, accompanied by phosphor-DRP1-S616 reduction and phosphor-DRP1-S637 elevation, which normalized mitochondrial fission.
“Melatonin promoted cell survival via AMPKα activation, accompanied by phosphor-DRP1-S616 reduction and phosphor-DRP1-S637 elevation, which normalized mitochondrial fission [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
All beneficial effects of melatonin on microvasculature were abolished in AMPKα null mice.
“Notably, all the beneficial effects of melatonin on microvasculature were abolished in AMPKα null mice [134].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [134]
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- Authors
- Zhou, H., Zhang, Y., Hu, S., Shi, C., Zhu, P., Ma, Q., Jin, Q., Cao, F., Tian, F., & Chen, Y.
- Affiliations
- Chinese PLA General Hospital (CN)
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Department of Radiation Oncology Peking University Cancer Hospital and Institute Beijing China
- Corresponding author
- Chen, Yundai
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2017-04-27
- Volume
- 63
- Issue
- 1
- ISSN
- 0742-3098 (ISSN-L)
- 1600-079X
- PMC
- PMC5518188
- OpenAlex
- W2605501320
- Cited by
- 378
- References
- 41
- Citations by year
- 2026: 13 · 2025: 33 · 2024: 34 · 2023: 35 · 2022: 51 · 2021: 44 · 2020: 45 · 2019: 51 · 2018: 60 · 2017: 11 · 2013: 1
- FWCI
- 35.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Pineal Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81030002, 81270186, 81441008, 81102079)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- melatonin, cardiac microvasculature, ischemia-reperfusion injury, mitochondrial fission, Drp1, VDAC1, hexokinase 2, mitochondrial permeability transition pore, mitophagy, PINK1/Parkin pathway, AMPKα, endothelial cells, percutaneous coronary intervention, endothelial barrier, nitric oxide synthase
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Cardiotonic Agents, Heart, Hexokinase, Immunohistochemistry, Male, Melatonin, Myocardium, Myocardial Reperfusion Injury, Mice, Knockout, Mitochondrial Membrane Transport Proteins, Voltage-Dependent Anion Channel 1, Mice, AMP-Activated Protein Kinases, Microvessels, Mitochondrial Dynamics
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