ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1867; no. 5; p. 166088
• Main Authors: Hu, Yu-Feng, Wu, Chih-Hsun, Lai, Tsung-Ching, Chang, Yu-Chan, Hwang, Ming-Jing, Chang, Ting-Yung, Weng, Ching-Hui, Chang, Peter Mu-Hsin, Chen, Che-Hong, Mochly-Rosen, Daria, Huang, Chi-Ying F., Chen, Shih-Ann
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021
• Subjects: Aldehyde dehydrogenase 2; Aldehyde Dehydrogenase, Mitochondrial - physiology; ALDH22; Animals; Atrial Fibrillation - etiology; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Coenzyme Q10; Energy Metabolism; Gene Regulatory Networks; Male; Mice; Mitochondria - metabolism; Mitochondria - pathology; Mutation; Proteomics; SCN5A; Signal Transduction; Sodium Channels - genetics; Sodium Channels - metabolism; Transcriptome; RXRs; RARE; Transcriptome; CISD1; PPI; MDA; 4-HNE; ALDH2; SNP; Coenzyme Q10; ALDH22; CYC1; LVESD; SCN5A; CC; AF; ECG; GO; NRVMs; EP; LVEDD; PVDF; RA; PCC; SDS-PAGE; RARs; ROS; Proteomics; Aldehyde dehydrogenase 2; PCR
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2021.166088

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid β-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype. [Display omitted] •The ALDH2*2 increased atrial fibrillation (AF) susceptibility in the mice model.•Concurrent dysregulated SCN5A channel and mitochondrial bioenergetics led to AF.•Coenzyme Q10 protected against AF attack in humans characterized by ALDH2*2 genotype.