Mitochondrial energy metabolism in heart failure: a question of balance
Huss, et al.



"Oxidation of fatty acids (FAs) and glucose in mitochondria accounts for the vast majority of ATP generation in the healthy adult heart. FAs are the preferred substrate in the adult myocardium, supplying about 70% of total ATP. FAs derived from circulating triglyceride-rich lipoproteins and albumin-bound nonesterified FAs are oxidized in the mitochondrial matrix by the process of FA beta-oxidation (FAO), whereas pyruvate derived from glucose and lactate is oxidized by the pyruvate-dehydrogenase (PDH) complex, localized within the inner mitochondrial membrane. Acetyl-CoA, derived from both pathways, enters the tricarboxylic acid (TCA) cycle. Reduced flavin adenine dinucleotide (FADH2) and NADH are generated via substrate flux through the beta-oxidation spiral and the TCA cycle, respectively. The reducing equivalents enter the electron transport chain, producing an electrochemical gradient across the mitochondrial membrane that drives ATP synthesis in the presence of molecular oxygen (oxidative phosphorylation)."



Figure 1
Pathways involved in cardiac energy metabolism. FA and glucose oxidation are the main ATP-generating pathways in the adult mammalian heart. Acetyl-CoA derived from FA and glucose oxidation is further oxidized in the TCA cycle to generate NADH and FADH2, which enter the electron transport/oxidative phosphorylation pathway and drive ATP synthesis. Genes encoding enzymes involved at multiple steps of these metabolic pathways (i.e., uptake, esterification, mitochondrial transport,and oxidation) are transcriptionally regulated by PGC-1α with its nuclear receptor partners, including PPARs and ERRs (blue text). Glucose uptake/oxidation and electron transport/oxidative phosphorylation pathways are also regulated by PGC-1α via other transcription factors, such as MEF-2 and NRF-1. Cyt c, cytochrome c.


Figure 3
Cardiac energy substrate selection is a dynamic balance influenced by developmental, physiological, and pathological cues. In the fetal heart, glucose oxidation is favored, whereas FA oxidation serves as the major ATP-generating pathway in the adult myocardium. Significant shifts in substrate preference occur in response to dietary (insulin) and physiological (exercise) stimuli. Certain pathophysiological contexts, such as hypertrophy and ischemia, drive metabolism toward glucose utilization, whereas in uncontrolled diabetes, the heart utilizes FAs almost exclusively. In some cases, as in early response to pressure overload–induced hypertrophy, these metabolic shifts are thought to be protective. Alterations in activity or expression of nuclear receptors (PPARs and ERRs) and PGC-1α mediate these shifts in energy substrate utilization.

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