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

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 these evidences of the cardiac pathologies that come from reduced mitochondrial FAO, the shift from FAO to glucose in the hypertrophied heart may be beneficial and adaptive for the short term. PPARα-null mice, for example, have reduced FAO efficiency, but the hearts showed no ventricular dysfunction. However, in a rat pressure overload model, when FAO was reactivated, the hearts developed ventricular dysfunction [88]. In addition, the degree and duration of the pathophysiological stimulus as well as the systemic metabolic state (e.g., levels of circulating lipids) may contribute to the consequence of alterations of FAO capacity in the pathogenesis of HF.
