Can Chaotic Activity of Mitochondrial Energetics be at the Origin of Cardiac Arrhythmias?

JACKELYN M. KEMBRO; MIGUEL A. AON; SONIA CORTASSA

Orlando

Simposio; NINETEENTH ANNUAL CARDIOVASCULAR DIVERSITY RESEARCH SUPPLEMENT AWARDEE SESSION; 2011

National Heart Lung and Blood Institute

Mitochondrial dysfunction through oxidative stress and compromised energy supply may be at the origin of cardiac arrhythmias. Under acute heart failure, high levels of reactive oxygen species (ROS) emission from mitochondria happen that, after a threshold is attained, can drive whole cell oscillations and potentially escalate to the whole heart leading to conduction block and fatal arrhythmias. We propose that chaotic dynamics in mitochondrial energetics is at the origin of cardiac fibrillation, which is a novel proposal with respect to reported experimental evidence suggesting an electrophysiological origin of chaos in the heart. Existing evidence indicates that diabetic cardiomyopathy involves dysfunctional mitochondrial energetic and redox functions, resulting in deficient signaling. In this context, we are exploring the possibility that a higher propensity to arrhythmias in diabetes originate from chaotic or complex oscillations of mitochondrial energetics, under conditions that may prevail under reperfusion following acute myocardial ischemia. In this work, we are using a computational model of mitochondrial energetics to characterize complex temporal dynamics under conditions of oxidative stress. A previous model of mitochondrial energetics has been upgraded to include ROS production in the respiratory chain and ROS scavenging in both mitochondrial and cytoplasmic compartments. Stability analysis of the model shows that during respiratory state 4, mitochondrial oscillations are observed when O2.− scavenging capacity is compromised in both compartments, or when O2.− production is increased. The oscillatory regime comprises large amplitude cycles of DYm, NADH, O2.−, and H2O2. Return plots show that these oscillations are complex, exhibiting positive maximum Lyapunov exponents, a signature of chaos. Utilizing the predictive capabilities of the isolated mitochondrion model, we plan its integration into the Excitation-Contraction coupling-model of cardiomyocyte function. An analysis of the effects of mitochondrial chaos on the electro-mechanical behavior of cardiomyocytes will be performed