Mitochondrial Dysfunction in the Aging Heart
Mitochondria are the powerplants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) used to power cell activities. With age, mitochondria become less effective in this task, producing less ATP and increased amounts of oxidative byproducts, adding to cell stress. This is the result of damage to mitochondrial DNA, less well protected and repaired than the DNA in the cell nucleus, combined with maladaptive changes in the expression of genes important to mitochondrial function and quality control. A reduced supply of ATP contributes to dysfunction in tissues and organs, particularly energy-hungry tissues such as muscle and brain.
The mitochondrial electron transport chain (ETC) contributes 80%-90% of ATP in most mammalian tissues, making mitochondrial dysfunction detrimental due to reduced ATP production, indispensable for biological functions. Aging leads to alterations in ETC components, contributing to a number of age-related conditions. Hence, one of the consequences of the aging process is the drop in the efficiency of this energy production mechanism, leading to a decline in ATP production and subsequent cellular energy deficits. Dysfunctional mitochondria are increasingly associated with aged cardiovascular tissues.
Proper substrate utilization is imperative for the myocardium to fulfill its function, primarily relying on ATP (re-)synthesis through fatty acid oxidation within mitochondria. The myocyte employs additional pathways, such as glycolysis, creatine kinase, and adenylate kinase, in response to high ATP demand. During increased work, glycogen, glucose, and phosphocreatine are utilized to meet ATP demand, maintaining constant ATP levels. The efficiency of ATP production varies depending on substrate oxidation, with fatty acid oxidation producing more ATP. This metabolic plasticity diminishes in chronic pathologies like congestive heart failure, impacting myocardial oxygen efficiency and causing intracellular ATP depletion.
Spare respiratory capacity, the ability to increase ATP production during heightened demand or reduced fuel supply, is crucial for cellular function and survival. Mitochondrial plasticity involves the efficiency of mitochondrial coupling and provides increased respiratory capacity under stress conditions. This phenomenon is particularly significant in ischemic injury and situations of augmented energy demand such as sepsis, endurance exercise, trauma, or heart failure. In the heart, aging leads to a decline in mitochondrial oxidative phosphorylation function. Increased electron leakage and mitochondrial ROS production contribute to oxidative damage, particularly affecting intrafibrillar mitochondria. Deficient mitochondrial energetics, altered Ca2+ homeostasis, and excessive reactive oxygen species (ROS) generation contribute to reduced stress adaptability and augmented vulnerability to disease in the aged myocardium.