MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
Journal
Journal of Clinical Investigation
Journal Volume
130
Journal Issue
9
Pages
4663-4678
Date Issued
2020
Author(s)
Abstract
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. Copyright: ? 2020, American Society for Clinical Investigation.
Subjects
actin; calcium calmodulin dependent protein kinase II; calmodulin binding protein; holoenzyme; methionine monooxygenase; methionine sulfoxide reductase B; mical1 protein; unclassified drug; unspecific monooxygenase; actin binding protein; calcium calmodulin dependent protein kinase II; Drosophila protein; MICAL1 protein, human; Mical1 protein, mouse; mixed function oxidase; animal experiment; animal model; Article; autophosphorylation; binding affinity; cardiac muscle cell; cardiovascular mortality; catecholaminergic polymorphic ventricular tachycardia; circadian rhythm; controlled study; Drosophila melanogaster; female; gene editing; heart arrhythmia; heart function; heart output; heart protection; heart stress; induced pluripotent stem cell; locomotion; mouse; nonhuman; oxidation reduction state; oxidative stress; priority journal; stereospecificity; amino acid substitution; animal; cardiac muscle; cell line; enzymology; genetics; heart ventricle tachycardia; human; knockout mouse; metabolism; missense mutation; oxidation reduction reaction; pathology; Amino Acid Substitution; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Line; Drosophila melanogaster; Drosophila Proteins; Humans; Mice; Mice, Knockout; Microfilament Proteins; Mixed Function Oxygenases; Mutation, Missense; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Tachycardia, Ventricular
Other Subjects
actin; calcium calmodulin dependent protein kinase II; calmodulin binding protein; holoenzyme; methionine monooxygenase; methionine sulfoxide reductase B; mical1 protein; unclassified drug; unspecific monooxygenase; actin binding protein; calcium calmodulin dependent protein kinase II; Drosophila protein; MICAL1 protein, human; Mical1 protein, mouse; mixed function oxidase; animal experiment; animal model; Article; autophosphorylation; binding affinity; cardiac muscle cell; cardiovascular mortality; catecholaminergic polymorphic ventricular tachycardia; circadian rhythm; controlled study; Drosophila melanogaster; female; gene editing; heart arrhythmia; heart function; heart output; heart protection; heart stress; induced pluripotent stem cell; locomotion; mouse; nonhuman; oxidation reduction state; oxidative stress; priority journal; stereospecificity; amino acid substitution; animal; cardiac muscle; cell line; enzymology; genetics; heart ventricle tachycardia; human; knockout mouse; metabolism; missense mutation; oxidation reduction reaction; pathology; Amino Acid Substitution; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Line; Drosophila melanogaster; Drosophila Proteins; Humans; Mice; Mice, Knockout; Microfilament Proteins; Mixed Function Oxygenases; Mutation, Missense; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Tachycardia, Ventricular
Type
journal article