*3.1.3. Dysregulation of Ca2+ homeostasis*

ATP is manufactured, it is only partially broken down when sugar is metabolized anaerobically. Only a few moles of ATP can be resynthesized from the breakdown of sugar as compared to the yield possible when oxygen is present. In addition, there is an increase in hydrogen ions due to the formation of lactic acid, causing the muscle pH to decrease. This leads to acidosis

ther induce the inhibition of specific enzymes involved in metabolism and muscle contraction. The aerobic system includes the Krebs cycle and the ETC. Mitochondria are crucial for the working of the cardiomyocytes as these powerhouses provide the aerobic metabolism for the cardiomyocyte function. Reduced mitochondrial oxidative capacity has been observed in rodent HF models. The onset of HF is not an overnight process but a progression of continual abnormalities in the bioenergetics due to the disruption of metabolic regulatory signaling pathway or the lack of oxygen supply, which leads to failure in mitochondrial dysfunction

Numerous studies have demonstrated that cardiac substrate preference is altered in the failing heart. Fatty acids are the preferential energy substrates of the heart and contribute to 60–90% of cardiac ATP production [74]. At the early phase of HF, there is a decline in FAO. An adaptive mechanism is to switch from fatty acid to glucose via the glycolytic pathway. The decrease in the capacity for the mitochondria to oxidize fatty acids is linked to the reduced expression of the master regulator of energy metabolism in mitochondria, PGC-1α (transcriptional co-activator peroxisome proliferator–activated receptor-γ coactivator-1α) [75–77]. In mouse model, PGC-1α is shown to be crucial for the functional efficiency of mitochondrial FAO, lipid regulation, and ATP synthesis, particularly in instances of increased cardiac demand [78]. The overexpression of PGC-1α in transgenic mice induces enhancement of mitochondrial respiration and an increase in mitochondrial numbers [79]. The downregulation of PGC-1α leads to reduction of its downstream targets, e.g., nuclear respiratory factor (NRFs), estrogen receptor–related receptor (ERRα/γ), peroxisome proliferator–activated receptors (PPARs), and subsequently regulates FAO, glucose utilization, and mitochondrial biogenesis [1, 69]. PPARα, as a transcription factor that enables fatty acids to be transported into the mitochondria and peroxisomes, is downregulated in failing hearts of animals and humans [80, 81]. In human HF patients (both ischemic and idiopathic DCM), ERRα and its target genes were downregulated,

which may contribute to the reduction of mitochondrial metabolic capacity [81].

It is yet unclear whether the myocardial substrate shifts serve as adaptive functions or cause deleterious effects on the failing heart, but the evidences from reports in animal models and in rare genetic human diseases provide some light. In mice studies, the rapid decline in the cardiac mitochondrial FAO capacity induces cardio-lipotoxic effects due to the accumulation of lipids [82, 83]. Furthermore, when FAO enzymes such as the very-long-chain acyl-CoA dehydrogenase (VLCAD) or the long-chain acyl-CoA dehydrogenase (LCAD) are disrupted in mice, cardiomyopathic profiles similar to human cases are observed [84, 85]. Likewise, with cardiac-specific deletion of the PPARβ gene, which is involved in the oxidation of the FA, the mice developed cardiomyopathy with cardiomyocyte apoptosis and death [86]. Moreover, in human cases, reports of deficiencies in children of enzymes that are part of the mitochondrial long-chain FAO have caused a stress-induced cardiomyopathy due to accumulation of myocardial lipids [87]. Despite

, and potassium ions that may fur-

and the accumulation of other metabolites such as ADP, Pi

*3.1.2. The shift of fuel selection of mitochondrial bioenergetics*

and decline in ATP production.

40 Mitochondrial Diseases

The reduction of energy production rate in dysfunctional mitochondria is also attributed by the dysregulation of Ca2+ homeostasis within the cardiomyocyte. Mitochondria act as a calcium sensor detecting the increase and decrease of the cytosolic Ca2+ to meet the needs of the cardiomyocyte. Ca2+ is transported into the mitochondria via MCU and out of the mitochondria via the sodium-calcium exchanger (NCX). Both the MCU and mitochondrial NCX are localized to the IMM. In normal physiological conditions, in the event of increased workload, the cytosolic Ca2+ is increased, triggering the opening of the MCU to transport Ca2+ into the mitochondrial matrix. The influx of the mitochondrial Ca2+ in the matrix increases the ATP synthase and the dehydrogenase activity of the citric acid cycle to generate more ATP [58]. Another transporter of Ca2+ into the mitochondria is the mPTP, which requires oxidative stress, elevated phosphate, and adenine nucleotide depletion to be opened. Increased uptake of Ca2+ into the mitochondria has been linked to cellular dysfunction and energy reduction [89, 90]. Also, the accumulation of Ca2+ in the mitochondria induces activation of the apoptotic and necrotic pathways [91]. In addition, in postmyocardial infarction HF mouse model, diastolic SR Ca2+ leak induces mitochondrial Ca2+ overload and dysfunction [92]. In HF, Ca/calmodulin-dependent protein kinase II (CamKII) has been involved in increasing mitochondrial Ca2+ uptake through the MCU and promotes mPTP opening and myocardial cell death [93].

#### *3.1.4. Impaired mitochondrial biogenesis*

Efficient mitochondrial capacity to meet the heart's workload also involves maintaining and protecting its biogenesis. It has been shown that the mitochondrial biogenesis was declined in failing heart, which is associated with the downregulation of the transcription factors such as NRF and ERRα [94].
