**2.2. Cardiac mitochondrial changes during cardiac development**

There are significant differences in mitochondrial metabolism and function during the cardiac development through the fetus, neonatal, and adult heart.

One of the major changes during the cardiac development is the use of energy fuels to generate ATP in cardiomyocyte. In the fetal heart, glucose and lactate are the predominant substrates used in the generation of ATP [43, 44]. The fetal heart boasts of a large endogenous glycogen supply, which is a significant source of the glucose on which the heart relies. Glycogenolysis is also particularly important in conditions of oxygen deprivation, allowing the fetal heart to resist the effects of hypoxia and ischemia better than the adult heart [43]. Fetal hearts have less mitochondria and therefore lower levels of respiratory and TCA cycle activities [2]. Notably, circulating levels of fatty acids are low, reducing the role of FAO in the generation of ATP. FAO is further inhibited by the high lactate levels present in the fetal heart [2]. Postnatally, an important switch occurs as fatty acids replace glucose and lactate as the primary energy substrates in the developing heart [43]. Consequently, the activity of the proteins of the carnitine shuttle, particularly the M isoform of the mitochondrial carnitine palmitoyltransferase I (CPT I) and mitochondrial carnitine palmitoyltransferase II (CPT II), is markedly increased during the early postnatal period [45]. Other key proteins that have been associated with the uptake of fatty acids into cardiac muscle cells also exhibit increased mRNA expression during maturation of the heart, reflecting increased fatty acid uptake and metabolism [46].

In addition, there is a change in the transfer and use of the energy currency in the mitochondria during the cardiac development. MitoCK is responsible for the production of high-energy phosphates in adult heart. In the fetal heart, mitoCK levels are undetectable, with its expression starting between weeks 1 and 2 in the Wistar rat pup and rising to adult levels after 6 weeks [47]. MitoCK expression was associated with creatine-activated respiration and the affinity of OXPHOS to ADP. Importantly, there is a change in the organization of the cardiac mitochondria from a random arrangement from day 1 in a rat to a fine network of myofibrils by week 3, as mitoCK allows maximal activation of the processes of OXPHOS [47].
