**2. Cardiac energy metabolism: role of the mitochondria**

Cardiac energy metabolism relies on regular mitochondrial function and energy production. Thus, inborn errors of metabolism impacting the mitochondrial dysfunction are a common pathological factor of LVNC. Mitochondrial cardiomyopathy is a myocardial condition defined by an aberrant heart-muscle structure or function, that involves mitochondrial respiratory chain pathways. Failure in the regulation of these metabolic pathway mechanisms can lead to cardiac dysfunction associated with noncompaction [17]. Thus, the proper functioning of mitochondrial enzyme complexes is crucial for the normal progression of cardiac morphogenesis. This review focuses

specifically on the mitochondrial influence on trabecula morphogenesis and its influence on the compaction of LV myocardium. Moreover, we describe the mechanisms contributing to LVNC and explore the current diagnostic and therapeutic strategies available for this type of mitochondrial myopathy [18, 19].

A double membrane-bound organelle, mitochondria have their own genome and exhibit maternal inheritance patterns. The mitochondrial genome is composed of 22 tRNAs, 2 rRNAs, and 37 genes encoding 13 different proteins that form subunits of enzyme complexes within the oxidative phosphorylation system (OXPHOS). Although comparatively smaller than the nuclear genome, the human mitochondrial genome possesses thousands of mitochondria, each encoding dozens of copies of the mitochondrial genome. Unlike the nuclear genome, mitochondria have higher mutation rates (100 fold higher) due to the absence of a mismatch base repairing mechanism [20]. Notably, deficiencies in NADH-coenzyme Q (CoQ ) reductase (complex I) and cytochrome-c oxidase (complex IV) have been commonly studied in many mitochondrial disorders [20, 21]. OXPHOS pathway involves around 80 different proteins to make five electron transport complexes (complex I–V) [22]. Many of the mutations and defects in genes involved in OXPHOS impacts the mitochondrial energy production. As such they are the primary source of reactive oxygen species (ROS) generation. Hence, the overproduction of ROS causes mitochondrial damage through a range of pathologies that affects the rest of the cell (**Figure 2**). In addition to oxidative phosphorylation system, mitochondria also control apoptosis and cytosol calcium concentrations. Importantly within the cardiac muscle, calcium signaling propagated within the cytosol, is trafficked through the mitochondrial membrane via the voltage dependent anion channel (VDAC) and an inner membrane located calcium uniporter or a Na+ /Ca2+ exchanger. Thus, a vital feature of cellular life any alterations in mitochondrial Ca2+ homeostasis can cause profound effects in the mitochondrial function with defects contributing to cell death [23].

Mitochondrial energy production is influenced by maternally inherited mitochondrial DNA (mtDNA) and nuclear DNA [24] with mitochondrial gene mutations causing irregular function. Energy released upon electrons transfer between the 5 enzyme complexes of the mitochondrial electron transport chain (ETC) within the inner mitochondrial membrane, acts as a proton pump across the mitochondrial membrane. This electrochemical gradient is important for cellular energetic homeostasis [25]. Defects in the five enzyme complexes of mitochondrial ETC, some of which are encoded by mitochondrial DNA, can reduce ATP energy generation resulting in an energy insufficiency. Additionally, cardiac mitochondrial function is also coupled with ROS production from oxidative damage during the OXPHOS cycle. Elevated free iron levels and defective ETC as a result of the impaired intramitochondrial metabolism is associated with a vast increase in free radical generation leading to oxidative damage that could impact development.

Cardiomyocytes are composed of bundles of myofibrils containing myofilaments. The distinct, repeating micro units of myofibrils, sarcomeres, are the fundamental contractile units of the myocytes. The mitochondria in cardiomyocytes localized to sarcomeres form intracellular energetic unit (ICEU) [26]. Catabolism favors the movement of the chemical gradient from mitochondria in the form of ATP to sarcomeres. Composed of thin and thick filaments, the thick filamentous myosin motor protein component of the cardiac sarcomere is primarily responsible for force generation. While the structural abnormalities associated with LVNC has been well described, many of the details of its mechanism have yet to be elucidated. However, studies suggest a correlation between LVNC and myocardial abnormalities with

**Figure 2.**

*A variety of roles played by Mitochondria are critical for cellular maintenance: Energy production ("powerhouse of the cell"), OXPHOS pathway, alters between fusion and fission cycle, Ca2+ level control and apoptosis.*

energy generation, transfer and utilization as possible contributing factors to the irregular contraction and relaxation of cardiac muscles. As such, the impact of mitochondrial related gene deletion, mitochondrial function, and energy production cannot be overstated in light of the disorders arising from disruption of these processes and their impact on compaction at the early development of the LV myocardium.
