Mitochondrial Dysfunction in Cardiac Disease: The Fort Fell

Abstract

Myocardial cells and the extracellular matrix achieve their functions through the availability of energy. In fact, the mechanical and electrical properties of the heart are heavily dependent on the balance between energy production and consumption. The energy produced is utilized in various forms, including kinetic, dynamic, and thermal energy. Although total energy remains nearly constant, the contribution of each form changes over time. Thermal energy increases, while dynamic and kinetic energy decrease, ultimately becoming insufficient to adequately support cardiac function. As a result, toxic byproducts, unfolded or misfolded proteins, free radicals, and other harmful substances accumulate within the myocardium. This leads to the failure of crucial processes such as myocardial contraction-relaxation coupling, ion exchange, cell growth, and regulation of apoptosis and necrosis. Consequently, both the micro- and macro-architecture of the heart are altered. Energy production and consumption depend on the heart's metabolic resources and the functional state of the cardiac structure, including cardiomyocytes, non-cardiomyocyte cells, and their metabolic and energetic behavior. Mitochondria, which are intracellular organelles that produce more than 95% of ATP, play a critical role in fulfilling all these requirements. Therefore, it is essential to gain a deeper understanding of their anatomy, function, and homeostatic properties.

Keywords: cardiac disease; energy; heart failure; mitochondria.

Figure 1

Changes in mitochondrial function and structure occur throughout the progression of heart failure syndrome. As heart failure advances, vacuolar degeneration of the mitochondria becomes evident, along with increased membrane permeability, altered biochemical substrate utilization, and heightened production of free radicals. Although defensive mechanisms increase in response to these changes, they eventually become insufficient to prevent the impending decompensation as the syndrome worsens. Ultimately, the heart’s defenses are overwhelmed, leading to failure. The fort fell. p: preserved, r: reduced, ↑: increase, ↓: decrease, ↑↑: bigger increase, ↓↓: bigger decrease, ↓↓↓ much bigger decrease.

Figure 2

The primary functions of mitochondria are the production of adenosine triphosphate (ATP) and the release of reactive oxygen species (ROS). These functions are regulated by proteins involved in mitochondrial shaping, which are governed by the processes of fission and fusion, each controlled by specific proteins. Fission is associated with mitochondrial morphological changes, while fusion is linked to processes such as mitophagy, apoptosis, and energy production. Together, these systems ensure proper mitochondrial function and cellular homeostasis.

Figure 3

Mitochondrial function is crucially dependent on several factors: the efficient utilization of metabolic resources, proper communication with other organelles, regulated ion exchange, minimal accumulation of free radicals and harmful byproducts, and the ability to control cell necrosis and apoptosis. Protective mechanisms such as mitochondrial fission and fusion play an essential role in maintaining mitochondrial integrity and function. These processes help adapt to cellular stress and damage, ensuring the organelles continue to operate normally. However, when these protective mechanisms fail—whether due to a breakdown in homeostasis or malfunctioning of the fission and fusion processes—mitochondrial dysfunction ensues. This dysfunction marks the onset of heart failure syndrome, which progressively worsens over time as the mitochondria can no longer sustain normal cellular function.