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

Abstract

Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.

Effects of cGMP/Akt/GSK-3β signaling pathway on atrial natriuretic peptide secretion in rabbits with rapid atrial pacing

“…In this study, we observed that rapid pacing led to atrial mitochondrial damage, which influence ATP production and GC activity as ATP can enhance GC activity (Duda, 2010). RAP leads to mitochondrial DNA damage in atrial myocytes and the impairment of mitochondrial oxidative phosphorylation function (Pool et al, 2021), it eventually result in the disorder of ATP synthesis and the imbalance of energy metabolism in atrial myocytes, which may be one of the reasons for the decrease of PGC activity. Therefore, the sensitivity of NPR-A to ANP and PGC activity decreased during RAP, resulting in reduced cGMP production.…”

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

“…In cardiomyocytes, the cytoskeleton is highly specialized, consisting of actin filaments, desmin (intermediate) filaments, and microtubules, interacting with membrane-associated proteins, sarcomeric and nuclear proteins, and proteins of the intercalated disk. This complex network, which also interacts with various organelles, including sarcoplasmic reticulum (SR), mitochondria, and the nucleus, plays an important role in the transmission of signals and the transport of (ubiquitinated) proteins within the proteostasis network [6,19,22] (Figure 2). Within the proteostasis network, especially the Emerging research findings indicate a prominent role of genetic variations mainly in ion channel and cytoskeletal (-associated) genes in driving AF [15].…”

Integrating Evidence of the Traditional Chinese Medicine Collateral Disease Theory in Prevention and Treatment of Cardiovascular Continuum

“…However, metabolic syndrome (MS) is closely related to an increased morbidity of arrhythmia in various pathophysiological aspects ( Kumar and Gehi, 2012 ; Gawałko et al, 2021 ; Joseph et al, 2021 ; Pool et al, 2021 ). A large cohort study showed that metabolic factors including obesity, hypertension, low LDL-C level, and impaired fasting blood glucose level are closely related to new-onset atrial fibrillation (AF) ( Watanabe et al, 2008 ).…”