Nuclear Genes Causing Mitochondrial Cardiomyopathy

Abstract

The heart functions to pump blood throughout the body and is capable of adjusting the frequency and intensity of its repetitive contractions to meet energetic demands. Cardiac myocytes are connected in series and, unlike skeletal muscle fibers, do not assemble in parallel arrays but bifurcate and join to form a three-dimensional network [1][2][3][4]. Mitochondria occupy greater than 30 % of cardiomyocyte volume and are organized in densely packed rows under the sarcolemma and between myofilaments. This ordered arrangement ensures that a constant diffusion distance exists between mitochondria and the core of the myofilament. The myofibrils are formed by repeating sarcomere units. The sarcomeres are the basic contractile units and are composed of thin filaments consisting of cardiac actin, alpha tropomyosin, and troponins T, I, and C and thick filaments composed of myosin heavy chain, myosin light chains, and myosin-binding proteins C, H, and X. Myosin heavy chain contains the ATPase activity that drives cardiac contraction.The heart is one of the major energy-consuming organs. Energy is primarily stored in the form of ATP or phosphocreatine, which is formed by creatine kinasemediated phosphorylation of creatine by ATP. Overall, the heart uses approximately 1 mM ATP per second and requires complete energy substrate renewal about every 20 seconds. [5]. The heart is promiscuous in its utilization of energy substrates and can use fatty acids, carbohydrates, lactate, ketone bodies, or amino acids. Prenatally, energy is primarily derived from glucose as the substrate undergoing glycolysis. At the time of birth, the myocardium switches from anaerobic glycolysis to fatty acid oxidation and oxidative phosphorylation as a means of ATP production [6,7]. Fatty acids remain the preferred substrate throughout postnatal life. Mouse models have demonstrated that there is a strong activation of mitochondrial biogenesis in