Na⁺ homeostasis is very important for cardiomyocyte functioning such as excitation-contraction coupling (ECC) and metabolism; however, the human Na_V1.5-F1759A gain-of-function mutation has been associated with the pathogenesis of atrial fibrillation (AF). We hypothesized that intracellular Na⁺ influx may disturb Na⁺/Ca²⁺ exchanger activity in the plasma membrane and inner mitochondrial membrane, which may together disrupt intracellular Ca²⁺ signalling and mitochondrial function, ultimately leading to increased mitochondrial reactive oxygen species (ROS) production. To address this hypothesis, we studied the recently established double-transgenic (dTG) mouse model FLAG-Na_V1.5-F1759A, expressing the transgenes under the control of the cardiac specific αMHC promotor and backcrossed in the mitochondrial redox-competent C57Bl/6N background. Kaplan-Meier survival analysis of 47 wild type control and 46 dTG animals showed an overall mortality of 40 % after 12 weeks, which was pronounced in male compared to female mice. During 10-minute 6-lead ECG recordings, spontaneous episodes of intermittent AF were confirmed in all dTG animals. Transthoracic echocardiography measurements demonstrated significant structural and functional changes of the atria in 8 weeks old mice, e.g. increased left atrial inner diameters (LA ID: 2.54 ± 0.12 mm in dTG vs. 1.70 ± 0.04 mm in WT, p <0.0001) and depressed left atrial fractional shortening (LA FS: 3.49 ± 0.50 % in dTG vs. 17.19 ± 1.12 % in WT, p<0.0001). In addition, we identified a moderately decreased left-ventricular systolic function, which is in line with arrhythmia-induced cardiomyopathy in dTG mice. Confocal bright-field imaging of isolated atrial and ventricular myocytes showed an increased cellular size and length size and length that confirmed atrial and not ventricular hypertrophic remodelling. Confocal live-cell membrane imaging revealed changes in the transverse-axial tubule network with significantly decreased transverse vs. increased axial tubule components, suggesting subcellular ECC defects. Intracellular Na⁺ measurement with ²³Na NMR confirmed higher [Na⁺]_i levels in the dTG mice under physiological conditions (WT: 4.26 ± 0.4, dTG: 5.3 ± 0.4 AU, p<0.05) driving the AF phenotype. Metabolic profiling of ventricular tissue by ¹H NMR showed a significant increase of lactate and a reduction of high-energy metabolites (ATP and NADP) of transgenic mice suggesting metabolic impairments. Furthermore, tandem mass tags (TMT) labelling approach was used for quantitative proteomic readouts, the data shows significant changes in proteins involved in the metabolic pathways and electron transport chain in the dTG mice atria implying disturbances in cardiac metabolism. For live-cell mitochondrial ROS imaging, we crossed the AF mouse model FLAG-Na_V1.5-F1759A with redox biosensor mice expressing mitochondrial matrix-targeted roGFP to measure the glutathione redox potential E_GSH.  Interestingly, atrial myocytes of triple transgenic (TTG) biosensor mice showed a significantly decreased glutathione redox potential E_GSH (E_GSH: -296.30 ± 2.0mV in TTG vs. -284.90 ± 1.5 mV in WT, p <0.0001). Taken together, these findings are consistent with the hypothesis that intracellular Na⁺ via NaV1.5 causes increased mitochondrial matrix oxidation and ROS production that not only alters the ECC but also impairs mitochondrial energy metabolism, which may induce maladaptive atrial remodelling and perpetuates atrial fibrillation.