Clinical & Experimental Cardiology
Open Access

Mitochondrial Dysfunction in Cardiac Disease: Therapeutic Implications

Rafal Bogacki^{* *}Correspondence: Rafal Bogacki, Department of Cardiology, Jagiellonian University, Krakow, Poland, Email:

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Description

Mitochondria, often termed the powerhouses of the cell, play a central role in cardiac function through their critical involvement in energy production, calcium homeostasis, Reactive Oxygen Species (ROS) generation, and cell death pathways. The heart, with its exceptionally high energy demands, contains one of the highest volumes of mitochondria in the body, accounting for approximately 30% of cardiomyocyte volume. Given this fundamental dependence on mitochondrial function, it is unsurprising that mitochondrial dysfunction has emerged as a key contributor to various cardiac pathologies, including ischemic heart disease, heart failure, diabetic cardiomyopathy, and inherited mitochondrial disorders.

In the healthy heart, mitochondria primarily generate Adenosine Triphosphate (ATP) through oxidative phosphorylation, utilizing substrates derived from fatty acid oxidation, which accounts for 60%-90% of cardiac energy production under normal conditions. This process is tightly regulated to match energy supply with demand, ensuring efficient cardiac contractility and function. However, under pathological conditions, this delicate balance is disrupted, leading to alterations in mitochondrial bioenergetics, morphology, and quality control mechanisms.

Ischemia-reperfusion injury represents a classic example of mitochondrial dysfunction in cardiac disease. During ischemia, oxygen deprivation forces a shift from oxidative phosphorylation to anaerobic glycolysis, resulting in ATP depletion, intracellular acidosis, and calcium overload. Upon reperfusion, the sudden reintroduction of oxygen leads to excessive ROS production by damaged mitochondrial electron transport chain complexes, triggering mitochondrial Permeability Transition Pore (mPTP) opening. This critical event causes further mitochondrial swelling, membrane rupture, and release of pro-apoptotic factors, ultimately contributing to cardiomyocyte death and myocardial injury.

In chronic heart failure, mitochondrial abnormalities are characterized by decreased oxidative capacity, altered substrate utilization, and impaired energy transfer. The failing heart exhibits a shift from fatty acid oxidation to glucose utilization, reminiscent of the fetal metabolic profile-a change initially considered adaptive but increasingly recognized as contributory to disease progression. This metabolic remodeling is accompanied by decreased activity of electron transport chain complexes, reduced mitochondrial density, and abnormal mitochondrial morphology. The ensuing energy deficit contributes to impaired contractile function, while increased ROS production promotes oxidative damage to cellular components, including mitochondrial DNA, further exacerbating the cycle of dysfunction.

Diabetic cardiomyopathy presents another distinct pattern of mitochondrial impairment characterized by paradoxical metabolic inflexibility with overdependence on fatty acid oxidation, mitochondrial uncoupling, and excessive ROS generation. Hyperglycemia-induced post-translational modifications of mitochondrial proteins such as advanced glycation end products, further compromise mitochondrial function. Additionally, impaired mitophagy-the selective autophagy of damaged mitochondria-results in accumulation of dysfunctional organelles, perpetuating oxidative stress and cellular damage.

Beyond these acquired conditions, inherited mitochondrial cardiomyopathies arise from mutations in either mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins. These disorders often present with multisystemic manifestations but may predominantly affect cardiac tissue due to its high energy requirements. Examples include Kearns-Sayre syndrome, mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes (MELAS), and Barth syndrome, the latter resulting from mutations in the tafazzin gene leading to abnormal cardiolipin remodeling and mitochondrial structural abnormalities. The recognition of mitochondrial dysfunction as a central element in cardiac pathophysiology has stimulated research into therapeutics targeting various aspects of mitochondrial biology. Several promising approaches are under investigation, ranging from direct modulation of mitochondrial energetics to enhancement of mitochondrial quality control mechanisms.

Conclusion

Metabolic modulators aim to optimize substrate utilization and enhance energetic efficiency. Trimetazidine and ranolazine partially inhibit fatty acid oxidation, shifting metabolism toward glucose utilization, which requires less oxygen per ATP produced-a potentially beneficial adaptation in ischemic conditions. Perhexiline, another metabolic modulator, inhibits carnitine palmitoyltransferase-1, the rate-limiting enzyme for fatty acid transport into mitochondria, with similar effects on substrate preference. Clinical studies have demonstrated improvements in cardiac function and exercise capacity with these agents, particularly in patients with angina or heart failure. Mitochondrial antioxidants represent another therapeutic approach, directly targeting excessive ROS production.