From mitochondrial dynamics to arrhythmias

Abstract

The ROS-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell wide collapse of the mitochondrial membrane potential, ΔΨm, visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in ΔΨm, NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of ΔΨm under criticality leads to: i) energetic failure, ii) temporal and regional alterations in action potential (AP), iii) development of zones of impaired conduction in the myocardium, and, ultimately, iv) a fatal ventricular arrhythmia.

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

“…Under physiological conditions, Ͼ90% of energy production required for heart function comes from mitochondria and is dependent on activity of the multisubunit complexes forming the ETC (complexes I-IV) that generates the proton-motive force driving ATP synthesis through complex V. The activities of the ETC and ATP synthesis are tightly regulated to match ATP supply and demand in the heart during physiological workload (22). Any alteration in mitochondrial function is therefore expected to reduce the energetic reserves and disturb homeostatic balance during stress, resulting in impairment of cardiac electrical and mechanical functions (1,5,10,11,48,59) and, Fig. 2.…”

“…However, information pertaining to derangement in the OXPHOS in human AF compared with a well-matched group without AF is lacking. This is important because conditions that predispose to AF-such as aging, hypertension, coronary artery disease, heart failure, or ventricular or atrial dysfunction-can by themselves contribute to mitochondrial dysfunction and must be accounted for when estimating the impact of AF on mitochondrial function (5,11,15,17). Moreover, it is not clear whether reported changes in myocardial energetics and mitochondrial function (1,27,56) are causative or the consequence of AF or associated conditions; nor is it clear whether the OXPHOS impairment reported in some (32) but not all (5a) animal studies also occurs in the human atria (12,37,50).…”

Testosterone deprivation accelerates cardiac dysfunction in obese male rats

“…The possible mechanism could be due to the increasing level of plasma and cardiac MDA, and increased cardiac mitochondrial ROS production in HFO rats. The increase in the level of oxidative stress in the heart may have aggravated an apoptotic pathway (Zorov et al 2006) and led to a decrease in anti-apoptotic (BCL2) levels, and an increase in pro-apoptotic protein (BAX) levels (Pongkan et al 2015), therefore, leading to cardiomyocyte apoptosis and finally LV dysfunction (Aon et al 2009). …”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…RIRR is a mechanism for ROS amplification and regional ROS generation. The process involves the opening of two different channels in the mitochondrial inner membrane: the mitochondrial permeability transition pore (mPTP) and the inner membrane anion channel (IMAC) (Aon et al, 2009;Zorov et al, 2014). Opening of the pores (e.g., upon elevated Ca 2+ or ROS levels) may, among other responses [e.g., a dissipation of the mitochondrial inner membrane potential ( m), a ceased production of ATP, etc.…”