MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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Enthalten in: |
The Journal of clinical investigation - 130(2020), 9 vom: 01. Sept., Seite 4663-4678 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Konstantinidis, Klitos [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 08.02.2021 Date Revised 28.07.2023 published: Print Citation Status MEDLINE |
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doi: |
10.1172/JCI133181 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM313245169 |
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245 | 1 | 0 | |a MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII |
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520 | |a Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, N.I.H., Intramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
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650 | 4 | |a Cardiology | |
650 | 4 | |a Cell Biology | |
650 | 4 | |a Molecular biology | |
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700 | 1 | |a Bezzerides, Vassilios J |e verfasserin |4 aut | |
700 | 1 | |a Lai, Lo |e verfasserin |4 aut | |
700 | 1 | |a Isbell, Holly M |e verfasserin |4 aut | |
700 | 1 | |a Wei, An-Chi |e verfasserin |4 aut | |
700 | 1 | |a Wu, Yuejin |e verfasserin |4 aut | |
700 | 1 | |a Viswanathan, Meera C |e verfasserin |4 aut | |
700 | 1 | |a Blum, Ian D |e verfasserin |4 aut | |
700 | 1 | |a Granger, Jonathan M |e verfasserin |4 aut | |
700 | 1 | |a Heims-Waldron, Danielle |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Donghui |e verfasserin |4 aut | |
700 | 1 | |a Luczak, Elizabeth D |e verfasserin |4 aut | |
700 | 1 | |a Murphy, Kevin R |e verfasserin |4 aut | |
700 | 1 | |a Lu, Fujian |e verfasserin |4 aut | |
700 | 1 | |a Gratz, Daniel H |e verfasserin |4 aut | |
700 | 1 | |a Manta, Bruno |e verfasserin |4 aut | |
700 | 1 | |a Wang, Qiang |e verfasserin |4 aut | |
700 | 1 | |a Wang, Qinchuan |e verfasserin |4 aut | |
700 | 1 | |a Kolodkin, Alex L |e verfasserin |4 aut | |
700 | 1 | |a Gladyshev, Vadim N |e verfasserin |4 aut | |
700 | 1 | |a Hund, Thomas J |e verfasserin |4 aut | |
700 | 1 | |a Pu, William T |e verfasserin |4 aut | |
700 | 1 | |a Wu, Mark N |e verfasserin |4 aut | |
700 | 1 | |a Cammarato, Anthony |e verfasserin |4 aut | |
700 | 1 | |a Bianchet, Mario A |e verfasserin |4 aut | |
700 | 1 | |a Shea, Madeline A |e verfasserin |4 aut | |
700 | 1 | |a Levine, Rodney L |e verfasserin |4 aut | |
700 | 1 | |a Anderson, Mark E |e verfasserin |4 aut | |
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