MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
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
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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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 1

The redox state of CaMKII M308 is set by MICAL1 and MSRB to control CaM binding.

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The redox state of CaMKII M308 is set by MICAL1 and MSRB to control CaM ...
(A) Enzymatic activity of MICAL1 as measured by NADPH absorbance at 340 nm in the absence and presence of CaMKII with increasing concentrations of NADPH. The curves represent nonlinear regression fit derived from experimental data (curves are derived from n = 14 or 15 experimental measurements in each group; each data point represents the average of n = 2–3 measurements at different NADPH concentrations. (B) Mass spectrometry showing a +16-Da shift in the mass of WT CaMKII after incubation with MICAL1 and NADPH (bottom panel) but not with NADPH only (top panel). (C) Methionine sulfoxide reductase B (MSRB) reverses the +16-Da shift in the mass of WT CaMKII treated with MICAL1 and NADPH. (D) Methionine sulfoxide reductase A (MSRA) does not reverse the +16-Da shift in the mass of WT CaMKII treated with MICAL1 and NADPH. (E) Mass spectrometry of CaMKII M308V mutant incubated with NADPH only (top panel). CaMKII M308V mutant does not exhibit a +16-Da shift in mass after incubation with MICAL1 and NADPH (bottom panel). Findings in B–E are representative of at least 2 independent experiments. (F) Fluorescence anisotropy measurements show binding of FITC-labeled M308-sulfoxide (M308-SO) and WT peptides from CaMKII CaM-binding domain at various (n = 11) CaM concentrations. The curves represent nonlinear regression fit derived from the experimental data. Each data point represents the average of n = 2 measurements at each CaM concentration. (G) A schematic model in which the redox status of M308, set by MICAL1 and MSRB, regulates CaM binding, the requisite initial step for CaMKII activation.