Mitochondrial energy metabolism in heart failure: a question of balance

Abstract

The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure.

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 2

PGC-1α is an integrator of the transcriptional network regulating mitochondrial biogenesis and function. Numerous signaling pathways, including Ca²⁺-dependent, NO, MAPK, and β-adrenergic pathways (β₃/cAMP), activate the PGC-1α directly by increasing either PGC-1α expression or activity. Additionally, the p38MAPK pathway selectively activates PPARα, which may bring about synergistic activation in the presence of PGC-1α, whereas ERK-MAPK has the opposite effect. These signaling pathways transduce physiological stimuli, such as stress, fasting, and exercise, to the PGC-1α pathway. PGC-1α, in turn, coactivates transcriptional partners, including NRF-1 and -2, ERRα, and PPARα, which regulate mitochondrial biogenesis and FA-oxidation pathways. Dashed lines indicate activation mediated by signal transduction pathways in contrast to the coactivation by PGC-1α, which is denoted by solid lines. The arrows from ERRα to the NRFs and the PPAR complex indicate that ERRα activates these pathways at the level of expression.

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.