Age-related changes of myocardial ATP supply and demand mechanisms

Abstract

In advanced age, the resting myocardial oxygen consumption rate (MVO2) and cardiac work (CW) in the rat remain intact. However, MVO2, CW and cardiac efficiency achieved at high demand are decreased with age, compared to maximal values in the young. Whether this deterioration is due to decrease in myocardial ATP demand, ATP supply, or the control mechanisms that match them remains controversial. Here we discuss evolving perspectives of age-related changes of myocardial ATP supply and demand mechanisms, and critique experimental models used to investigate aging. Specifically, we evaluate experimental data collected at the level of isolated mitochondria, tissue, or organism, and discuss how mitochondrial energetic mechanisms change in advanced age, both at basal and high energy-demand levels.

Keywords: aging; bioenergetics; cardiac work; mitochondria; respiration.

Figure 1. Excitation-contraction-bioenergetics scheme in the heart

Majority of ATP is consumed by SERCA, Na⁺/K⁺ pump and contractile myofilaments. “Shuttlelike” diffusion of ADP and ATP in the cytosol is facilitated by CK and AK systems. In the cytosol, glucose is transformed to pyruvate, and fatty acids are converted to fatty acyl-coenzyme A. Pyruvate and fatty acyl-coenzyme A are, in turn, transported across the inner mitochondrial membrane to the mitochondrial matrix and are converted to acetyl-coenzyme A (pyruvate is oxidized by PDH, and fatty acyl-coenzyme by β-oxidation) while creating NADH and FADH₂. Acetyl-coenzyme A from both substrates is oxidized to carbon dioxide and water in the Krebs cycle, resulting in additional formation of NADH and FADH₂. The redox-potential energy of these reducing equivalents is, in turn, harnessed by the electron transport chain (complexes I–IV). Electrons are supplied to complex I in the form of NADH, and to complex II in the form of FADH₂. These redox electrons are passed downhill (in a energy-flow sense) to complex III by coenzyme Q. Electrons from complex III are transferred to complex IV by cytochrome c. The energy released from this electron flow is used to transport protons across the inner mitochondrial membrane, out from the matrix, creating a large electrochemical gradient across that membrane. Under normal conditions, the electron transport chain flux is paralleled by the M V̇O₂. The proton gradient and Δψ_m, form an electrochemical gradient of stored energy that is responsible to drive complex V to make ATP. ATP is transported to the cytosol across the inner mitochondrial membrane by ANT (in exchange for ADP, Pi and a proton) and the outer membrane by VDAC. The complement of ion transporters that maintain the other mitochondrial ionic gradients across the membrane, including the Ca²⁺ uniporter, Na⁺/Ca²⁺ exchanger and (regulated and unregulated) proton leak.

Figure 2. Changes in mitochondrial energetic mechanisms

While there is a wide array of evidence that mitochondrial energetic mechanisms decline in advanced age, the relative importance of these changes are still controversial. To better understand the source of this controversy we compared the changes in mitochondrial energetic mechanisms reported in both tissue (green) and isolated mitochondria (red) (see online supplement Table for extensive annotated listing and literature citations). The summary is separated into panels (A) basal conditions, and (B) high demand conditions. Note that the results in isolated mitochondria are often remarkably different than those from tissue. Moreover, in some cases the data are controversial even at the same level (i.e., tissue or isolated mitochondria) therefore a double arrow was used to reflect these existing discrepancies. Sometimes data are available only for isolated mitochondria and therefore a question mark was used for tissue data. Finally, two mitochondrial sub-populations (i.e., SSM and IFM) have been described in the myofilament compartments of cardiomyocytes and can be studied in isolated population. The age-dependent mitochondrial energy production is different for the two populations and therefore different symbols were used.