The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery

Figures

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  Figure 1. Schematic representation of ATP generation via fatty acid and glucose oxidation and leakage of reactive oxygen species in the mitochondria. Mitochondrial oxidative phosphorylation at the ETC is driven by the substrates NADH and FADH2, which originate predominantly from FA and carbohydrate oxidation. FAs pass the mitochondrial membrane as acyl-CoA by means of the carnitine acyltransferase membrane shuttles, consisting of CPT-1, CPT-2, and CACT. CPT1 converts acyl-CoA to acylcarnitine, which is subsequently transferred across the IMM by CACT. Inside the mitochondria, acylcarnitine is converted back into acyl-CoA by CPT-2. During β-oxidation, 2-carbon units are oxidized to produce acetyl-CoA, which is the substrate for the TCA cycle. Pyruvate traverses the mitochondrial membranes through VDAC and MPC. Once inside the mitochondrial matrix, pyruvate gets oxidized into acetyl-CoA to enter the TCA cycle. The reducing agents NADH and FADH2 are produced inside the TCA cycle. Electrons from NADH and FADH2 are donated to the complexes of the ETC, which translocate protons into the intermembrane space to establish a proton gradient for ATP synthesis. ROS are formed as by-products of the ETC.…

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  Figure 2. Schematic representation of Ca2+ transient handling and contraction in atrial cardiomyocytes and the role of SR and mitochondria. An action potential activates the Ca2+ channels in the T-tubule, resulting in an influx of Ca2+ into the cardiomyocytes. Subsequently, Ca2+ crosses the OMM through VDAC and is transported into the mitochondrial matrix via the MCU. Ca2+ efflux from the matrix is mediated by the NCLX. Cytosolic Ca2+ binds to cardiac troponin-C, which moves the troponin away from the actin binding site to form cross-bridges between actin and myosin. The myosin head binds to ATP and pulls the actin filaments towards the center of the sarcomere resulting in cardiomyocyte contraction. Dropping of the intracellular Ca2+ concentration returns the troponin complex to the resting position, thereby effectively inhibiting cardiac contraction and initiating relaxation.

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  Figure 3. Schematic overview of the pathophysiological processes during AF and the potential biomarkers and therapeutic implications. Mitochondrial dysfunction has been identified as a contributing factor in AF. Modulators of mitochondrial dysfunction such as 8-OHdG and cfc-mtDNA may aid in the staging of the severity of AF, predicting postoperative AF (POAF) onset, and the outcome of AF treatments. In addition, various pharmaceutical- and nutraceutical compounds are under investigation nowadays. Pharmaceutical compounds such as SS31, Ru360, or HSP inducer GGA and nutraceutical compounds such as NR, L-glutamine, and CoQ10 may present novel therapeutic strategies to counteract AF-induced mitochondrial dysfunction.