Mitochondrial CaMKII Plays Important Physiological and Pathological Roles

Calcium/calmodulin-dependent protein kinase II (CaMKII) is known for its roles in fight-or-flight responses, where it mobilizes ATP-consuming processes to maximize power output by regulating cellular Ca 2+ . We hypothesized that CaMKII may also influence ATP-generating processes in a feedforward mechanism to match ATP consumption with demand. Most cellular ATP is produced by oxidative phosphorylation (OXPHOS) in mitochondria; therefore, we generated transgenic animals whose mitochondrial CaMKII activity is boosted or inhibited by overexpressing mitochondrial targeted CaMKII (mtCaMKII), or a specific CaMKII inhibitor (mtCaMKII N ). We found that mitochondria from mtCaMKII mice have increased activity of pyruvate dehydrogenase and various TCA cycle enzymes. However, these mitochondria failed to provide sufficient ATP for cardiac function, likely due to detrimental remodeling of electron transport chain complex I. As a result, mtCaMKII mice develop a unique dilated cardiomyopathy soon after birth, which could be rescued by overexpressing the mitochondrial but not the myofibrillar form of creatine kinase. mtCaMKII N mice are protected against lipopolysaccharides (LPS)-induced mortality, ischemia/reperfusion injury, adverse cardiac remodeling after myocardial infarction and asthma. Furthermore, Drosophila melanogaster overexpressing mtCaMKII N have longer lifespan under heat stress (29 o C) and are resistant to paraquat, an ROS-inducing agent. However, in the mice, inhibiting mitochondrial CaMKII reduces metabolic fitness required to sustain the isoproterenol-induced fight-or-flight response, leading to elevated utilization of the cardiac glycogen store and increased lactate production. mtCaMKII N mice have reduced spontaneous activity and a higher tendency to gain fat mass when fed a high-fat diet; mtCaMKII N flies have a shorter lifespan in the absence of thermal stress (25 o C). We are using phosphoproteomics, metabolomics and in silico modeling approaches to determine the mechanisms by which mtCaMKII regulates energy metabolism and stress responses. Our results have provided important insights into the physiological and pathological roles of mitochondrial CaMKII.