1. MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
- Author
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Konstantinidis, Klitos, Bezzerides, Vassilios J., Lai, Lo, Isbell, Holly M., Wei, An-Chi, Wu, Yuejin, Viswanathan, Meera C., Blum, Ian D., Granger, Jonathan M., Heims-Waldron, Danielle, Zhang, Donghui, Luczak, Elizabeth D., Murphy, Kevin R., Lu, Fujian, Gratz, Daniel H., Manta, Bruno, Wang, Qiang, Wang, Qinchuan, Kolodkin, Alex L., Gladyshev, Vadim N., Hund, Thomas J., Pu, William T., Wu, Mark N., Cammarato, Anthony, Bianchet, Mario A., Shea, Madeline A., Levine, Rodney L., and Anderson, Mark E.
- Subjects
Tachycardia ,Actin ,Medical research ,Amino acids ,Heart ,Stem cells ,Calmodulin ,Muscle proteins ,Health care industry ,Johns Hopkins University ,Harvard University. Harvard Stem Cell Institute - 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 [Ca.sup.2+]/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 Drosophilamelanogaster, 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., Introduction [Ca.sup.2+]/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase with important roles in cardiovascular physiology and disease (1-4). Despite the critical role of CaMKII in fight-or-flight responses and human [...]
- Published
- 2020
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