CaMKII determines mitochondrial stress responses in heart

Abstract

Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress.

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

“…Furthermore, previous studies from our laboratory and others have shown that deregulated cytosolic ion handling perturbs mitochondrial energetics and leads to oxidative stress, which can positively feedback on CaMKII activity. Finally, recent studies suggested that CaMKII may directly phosphorylate mitochondrial ion channels such as the Ca 2+ uniporter,23 thus altering mitochondrial ion homeostasis and bioenergetics 23. Those components can be added to the ECME‐RIRR model in the future.…”

“…CaMKII is a multifunctional protein kinase ubiquitously expressed in cardiomyocytes and is activated by binding to Ca 2+ /CaM and subsequent autophosphorylation 19, 20. A growing body of evidence has demonstrated that CaMKII can also be activated by ROS 21, 22, 23, 24. Once activated, CaMKII can phosphorylate a wide range of key Ca 2+ and Na + regulatory proteins such as LCCs,25, 26, 27, 28 RyRs,29, 30, 31, 32, 33, 34, 35 phosphalamban,29, 34, 36 and Na + channels 37, 38.…”

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

“…The mitochondrial and cytosolic fraction was obtained from the supernatant by centrifugation at 10 700 g for 10 minutes twice. The pellet was resuspended in 500 μL of buffer without EGTA (pH 7.2 with KOH) 10, 21…”

“…Measured currents included the L‐type Ca 2+ current (I Ca,L ),23 K + current,24 and NCX current 25. MCU current (I MCU ) was recorded in the whole‐mitoplast voltage clamp configuration 10, 21…”

“…I MCU was recorded in whole‐mitoplast voltage clamp configuration 10, 21. Mitoplasts were perfused with solution containing the following (mmol/L): Na gluconate 150, HEPES 10, and CaCl 2 5 (pH 7.4, adjusted with NaOH).…”