The heart is highly dependent on continuous delivery of ATP to maintain contractile function. The normal postnatal heart generates 60-70% of high energy phosphates from the oxidation of fatty acids and 30-40% from the oxidation of glucose and other substrate. 95% of ATP is generated by oxidative substrate metabolism within mitochondria, which is mainly utilized by the myosin ATPases to maintain contractile function (Fig. 1). A minor part of ATP is used by enzymes and transporters to maintain cellular ion homeostasis. Thus, mitochondrial energy substrate metabolism is directly linked to contractile function and cellular homeostasis. Increasing evidence suggests a central role of mitochondrial dysfunction to contribute to contractile dysfunction in various cardiac pathologies, including heart failure, ischemia reperfusion injury, or diabetic cardiomyopathy. The development of therapeutic strategies to improve mitochondrial function is desirable but quite challenging, in part due to the incomplete understanding of mechanisms contributing to the development of mitochondrial dysfunction in cardiac disease. The goal of our group is to further elucidate the basic mechanisms regulating mitochondrial energetics in the heart, and to elucidate their contribution to cardiac disease.
Currently, we focus on the following topics:
1. Adiponectin and cardiac energy metabolism In recent years, numerous novel cytokines secreted by white adipose tissue were discovered, and altered serum levels of these cytokines have been linked with the development of obesity and Type 2 diabetes. In particular, reduced serum levels of adiponectin may contribute to the pathogenesis of insulin resistance and Type 2 diabetes. In addition, decreased serum levels of adiponectin increase the development of cardiac hypertrophy and increase the myocardial infarct size following ischemia reperfusion. Adiponectin is able to regulate signaling molecules that are of fundamental importance in the regulation of cellular energy metabolism, such as AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and sirtuin 1 (SIRT1). It is our goal to define the role of adiponectin in the regulation of cardiac energy metabolism, and to elucidate the signaling mechanisms by which impaired myocardial adiponectin action contributes to cardiac pathologies.
2. Sirtuins and cardiac energy metabolism Lysine acetylation of proteins is an evolutionarily conserved mechanism that influences fundamental cellular pathways in mammalian cells such as cell survival and energy substrate metabolism. Major regulators of protein acetylation are the members of the sirtuin family of NAD+-dependent deacetylases, which regulate target protein functions by reversibly changing their lysine acetylation status. Following identification of the founding member, saccharomyces cerevisiae silent information regulator (Sir) 2, seven mammalian orthologs have been described, termed sirtuin 1-7 (SIRT1-7). Intriguingly, some sirtuins have been shown to increase lifespan in lower organisms and mice, to regulate systemic glucose homeostasis and cellular energetics, and to exert cardioprotective effects. It is our goal to define the role of sirtuins in the regulation of cardiac energy metabolism, and to evaluate the contribution of impaired sirtuin action to the energy metabolic derangements in various cardiac pathologies.