MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
Klitos Konstantinidis, … , Rodney L. Levine, Mark E. Anderson
Klitos Konstantinidis, … , Rodney L. Levine, Mark E. Anderson
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(9):4663-4678. https://doi.org/10.1172/JCI133181.
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Research Article Cardiology Cell biology

MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII

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.

Authors

Klitos Konstantinidis, Vassilios J. Bezzerides, Lo Lai, Holly M. Isbell, An-Chi Wei, Yuejin Wu, Meera C. Viswanathan, Ian D. Blum, Jonathan M. Granger, Danielle Heims-Waldron, Donghui Zhang, Elizabeth D. Luczak, Kevin R. Murphy, Fujian Lu, Daniel H. Gratz, Bruno Manta, Qiang Wang, Qinchuan Wang, Alex L. Kolodkin, Vadim N. Gladyshev, Thomas J. Hund, William T. Pu, Mark N. Wu, Anthony Cammarato, Mario A. Bianchet, Madeline A. Shea, Rodney L. Levine, Mark E. Anderson

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Figure 5

M308 determines circadian rhythms and heart tube physiology in Drosophila melanogaster.

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M308 determines circadian rhythms and heart tube physiology in Drosophil...
(A) Representative actograms of WT and CaMKIIM308V flies. Actograms are double plotted with yellow bars representing light exposure. (B) CaMKIIM308V flies have a significantly longer free-running circadian period, as estimated by χ2 periodogram (WT n = 99, CaMKIIM308V n = 120). Bars denote mean ± SEM. (C) CaMKIIM308V flies exhibit significantly decreased average daily locomotion during constant darkness, as measured by beam-break counts per day (WT n = 99, CaMKIIM308V n = 120). Bars denote mean ± SEM. (D) Circadian χ2 amplitude indicates increased rhythm strength of CaMKIIM308V flies under constant darkness (WT n = 99, CaMKIIM308V n = 120). Bars denote mean ± SEM. (E) Representative M-mode kymograms generated from high-speed videos of beating WT and CaMKIIM308V fly heart tubes. Top panel shows cardiac cycle dynamics and heart wall contraction over time. Bottom panel shows individual systolic intervals of WT and CaMKIIM308V flies. CaMKIIM308V flies exhibit reduced wall movement distance (d) during systole and a prolonged time of shortening (ts) resulting in significantly diminished shortening speed. (F–I) CaMKIIM308V flies have markedly impaired heart function compared with WT flies. CaMKIIM308V flies at baseline exhibit (F) decreased cardiac output, (G) decreased fractional shortening, (H) decreased shortening speed, and (I) decreased relaxation rate (WT n = 33, CaMKIIM308V n = 30). (J) CaMKIIM308V heart tube diastolic diameter is markedly increased after intracellular Ca2+ chelation with EGTA-AM compared with WT heart tubes (WT n = 20, CaMKIIM308V n = 23). *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (B–D and F–I) or 2-tailed Mann-Whitney test (J).