Cellular and mitochondrial mechanisms of atrial fibrillation

Abstract

The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation-contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca²⁺) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca²⁺ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Keywords: Atrial cardiomyopathy; Atrial fibrillation; Calcium; Electrophysiology; Mitochondria; Oxidative stress.

Fig. 1

Results of a medical subject headings (MeSH) publication search in PubMed with categorisation. MeSH terms: “Atrial fibrillation” and “Mitochondria”. Relevant publications cited in the current review are also included. Review and editorial publications are excluded. Publications are listed in the Electronic Supplementary Material

Fig. 2

General mechanisms of atrial fibrillation and the potential involvement of disturbed mitochondrial Ca²⁺ handling. Re-entry requires a vulnerable substrate and trigger for initiation. Ectopic activity can maintain re-entry behaviour. APD, action potential duration; DAD, delayed afterdepolarisation (adapted from Heijman et al. [48])

Fig. 3

Dynamics of mitochondrial Ca²⁺. a Models of transmission of fast cytosolic Ca²⁺ transients ([Ca²⁺]_i) to mitochondrial Ca²⁺ ([Ca²⁺]_m). Model I: rapid, beat-to-beat transmission; Model II: slow integration of [Ca²⁺]_i oscillations. IMM, inner mitochondrial membrane; IMS, intermembrane space; OMM, outer mitochondrial membrane. b Fluorescent image of a Mitycam-infected human atrial myocyte (measurement of [Ca²⁺]_m.) c) Representative recording of Mitycam fluorescence in response to increasing stimulation frequency in a human atrial myocyte (unpublished). This figure was created using images from Servier Medical Art Commons Attribution 3.0 Unported License. (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License

Fig. 4

Major mitochondrial Ca²⁺-influx and -efflux pathways, mitochondrial ATP production and ROS elimination. Ca²⁺ is released by the sarcoplasmic reticulum (SR) via type 2 ryanodine receptors (RyR2) and passes through the outer mitochondrial membrane via voltage-dependent anion channels (VDAC). Ca²⁺ enters the mitochondrial matrix via the mitochondrial Ca²⁺ uniporter (MCU) in the inner mitochondrial membrane. Mitochondrial ryanodine receptor type 1 (RyR1) may play a role in taking up Ca²⁺ released more slowly from the SR via inositol 1,4,5-triphosphate receptors (IP₃R). Microdomains of high [Ca²⁺] are created due to the close proximity of SR and mitochondria through membrane tethering by mitofusin 1 and 2 (Mfn1 and Mfn2). Mitochondrial Ca²⁺ is extruded on the Na⁺/Ca²⁺/Li⁺ exchanger (NCLX). The mitochondrial permeability transmission pore (mPTP) opens upon Ca²⁺ overload and plays a role in cell death and ROS-induced ROS release (RIRR). Matrix Ca²⁺ activates Krebs cycle dehydrogenases, regenerating the reduced form of NADH (nicotinamide adenine dinucleotide) which donates electrons to the electron transport chain (ETC). Electron flow in the ETC causes protons to be translocated into the intermembrane space, contributing to an electrochemical gradient across the inner mitochondrial membrane (∆Ψ_m) which is used to drive ATP production by the F₁/F_o ATP-synthase (Complex V). Complexes I and III of the ETC produce superoxide (^∙O₂⁻) which is subsequently converted to H₂O₂ by superoxide dismutase (Mn-SOD). H₂O₂ is eliminated by peroxiredoxin (PRX) and glutathione peroxidase (GPX), which require reduced NADPH (nicotinamide adenine dinucleotide phosphate) for regeneration. NADPH is regenerated by isocitrate dehydrogenase (IDH) and malic enzyme (MEP) and nicotinamide nucleotide transhydrogenase (NNT). α-KG α-ketoglutarate, I–IV complexes I–IV of the ETC, Q Q-cycle, ΔpH proton gradient; mNHE, mitochondrial Na⁺–H⁺ exchanger, SERCA SR Ca²⁺-ATPase, GSH/GSSG reduced/oxidised glutathione, GR glutathione reductase, TRX_r/TRX_o reduced/oxidised thioredoxin, TR thioredoxin reductase (adapted from Nickel et al. [96])

Fig. 5

The impact of reducing mitochondrial ATP production. Compensatory increase in glycolysis reduces intracellular pH, consequently causing intracellular Na⁺ and Ca²⁺ overload (as suggested by Zima et al. [128]). I_Ca.L L-type Ca²⁺ current, NCX sodium–calcium exchanger, NHE sodium–hydrogen exchanger, RyR2 ryanodine receptor type 2, SCaEs spontaneous Ca²⁺ release events, SERCA SR Ca²⁺-ATPase

Fig. 6

Hypothesis of net ROS production during atrial fibrillation with a focus on mitochondrial Ca²⁺ handling. ATP requirement is increased during atrial fibrillation (due to increased workload), causing a “pull” on the electron transport chain (ETC) (left). Due to remodelling, there is inadequate mitochondrial Ca²⁺ ([Ca²⁺]_m) to sufficiently increase ATP production, e.g. NADH (nicotinamide adenine dinucleotide) production by the Krebs Cycle. NADPH (nicotinamide adenine dinucleotide phosphate) is converted to NADH by reverse mode NNT (nicotinamide nucleotide transhydrogenase) as a compensatory mechanism, at the expense of NADPH-driven ROS scavenging. Conversely, increased SR Ca²⁺ leak (right) could expose mitochondria to high Ca²⁺, thereby creating a “push” on the ETC and increasing mitochondrial ROS production such that it exceeds mitochondrial ROS scavenging capacity