Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

Abstract

Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross-sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an "an engine out of fuel" to "a defective engine on a path to self-destruction." This summary of evidence suggests that supplementation with micronutrients-preferably as a package rather than singly-might be a potential therapeutic strategy in the treatment of heart failure patients.

Keywords: deficiency; heart failure; micronutrients; mitochindrial dysfunction.

Fig. 1

Micronutrients in the mitochondrial electron transport change (mtETC). The electron transport chain (ETC) starts with a proton transfer (H⁺) mediated by complexes I and II, which promotes an electrochemical gradient across the mitochondrial membrane. Complex III (ubiquinol‐cytochrome c oxidoreductase or CIII) forms the central part of the mitochondrial respiratory chain, oxidizing CoQ10 and reducing cytochrome c while pumping protons from the matrix to the intermembrane space through the so‐called Q‐cycle mechanism. Finally, four cytochrome C molecules deliver an electron to complex IV (cytochrome c oxidase or CIV), being carried by the complex and transfer them to one dioxygen molecule, converting the molecular oxygen to two molecules of water. The electrochemical gradient is used by complex V (adenosine triphosphate [ATP] synthesis) to promote the generation of ATP from the available adenosine diphosphate (ADP). Although the ETC is a quite efficient mechanism to promote energy formation, the proton gradient generation results in an elevated reactive oxygen species (ROS) production due the O₂ oxidation into O₂ ⁻ (superoxide anion radical), H₂O₂ and OH (hydroxyl radical), which are the toxic products of respiration. Micronutrients present a key role in the proton gradient generation (CoQ10) and electron carrier transfer among the different complexes (Fe³⁺ and Cu⁺). Furthermore, Cu⁺, Zn^2– and Se²⁻ participate in the oxidant scavenger system, decreasing toxic mitochondrial ROS. Abbreviations: FADH2, flavin adenine dinucleotide; GPXs, glutathione peroxidases; GSH glutathione; reduced NADH, nicotinamide adenine dinucleotide; PRDX3, peroxiredoxin 3; SOD, superoxide dismutase; TXN2, thioredoxin 2; TXNRDs, thioredoxin reductases.