TY - JOUR
T1 - MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
AU - Konstantinidis, Klitos
AU - Bezzerides, Vassilios J.
AU - Lai, Lo
AU - Isbell, Holly M.
AU - Wei, An Chi
AU - Wu, Yuejin
AU - Viswanathan, Meera C.
AU - Blum, Ian D.
AU - Granger, Jonathan M.
AU - Heims-Waldron, Danielle
AU - Zhang, Donghui
AU - Luczak, Elizabeth D.
AU - Murphy, Kevin R.
AU - Lu, Fujian
AU - Gratz, Daniel H.
AU - Manta, Bruno
AU - Wang, Qiang
AU - Wang, Qinchuan
AU - Kolodkin, Alex L.
AU - Gladyshev, Vadim N.
AU - Hund, Thomas J.
AU - Pu, William T.
AU - Wu, Mark N.
AU - Cammarato, Anthony
AU - Bianchet, Mario A.
AU - Shea, Madeline A.
AU - Levine, Rodney L.
AU - Anderson, Mark E.
N1 - Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI133181
DO - 10.1172/JCI133181
M3 - Article
C2 - 32749237
AN - SCOPUS:85090250913
SN - 0021-9738
VL - 130
SP - 4663
EP - 4678
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -