Review
From mitochondrial dynamics to arrhythmias

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Abstract

The reactive oxygen species (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.

Introduction

Under metabolically stressful conditions such as substrate deprivation or oxidative stress, the role of mitochondrial function becomes a key arbiter of life and death at the cellular and organ level. While under normal physiological conditions the availability of energy is fine tuned to match changes in energy demand, under stress this is not the case. Most myocardial ATP production occurs in the mitochondria through oxidative phosphorylation, and most ATP utilization occurs at the myofibrils (Cortassa et al., 2006, Saks et al., 2007, Wallimann et al., 2007). Direct measures of ATP synthesis through creatine kinase in the human heart demonstrated a deficit in energy supply in clinical heart failure (Weiss et al., 2005). This reduction in ATP synthesis through CK is cardiac-specific and occurs in mild-to-moderate heart failure before a significant reduction in ATP can be detected.

The remarkable non-linear properties of the mitochondrial network, and of the heart itself, make them prone to the appearance of critical phenomena and bifurcations leading to self-organized, emergent, behavior. A dramatic example of the latter is the succession of failures shown to escalate from the mitochondrial network to the whole heart resulting in reperfusion-related arrhythmias after ischemic injury, and eventually the death of the organism (Akar et al., 2005, Aon et al., 2006a, O’Rourke et al., 2005). Mitochondria from heart cells act as a network of coupled oscillators, capable of producing frequency- and/or amplitude-encoded reactive oxygen species (ROS) signals under physiological conditions (Aon et al., 2006b, Aon et al., 2007b, Aon et al., 2008). This intrinsic property of the mitochondria can lead to a mitochondrial ‘critical’ state, i.e., an emergent macroscopic response manifested as a generalized Δψm collapse followed by synchronized oscillation in the mitochondrial network under stress (Aon et al., 2004). The large amplitude Δψm depolarization and bursts of ROS have widespread effects on all subsystems of the cell including energy-sensitive ion channels in the plasma membrane, producing an effect that scales to cause organ level electrical and contractile dysfunction. Mitochondrial ion channels appear to play a key role in the mechanism of this non-linear network phenomenon and hence are a potential target for therapeutic intervention.

The loss of Δψm is among the leading factors causing a rapid impairment of mitochondrial and cellular function that may result into necrotic or apoptotic cell death (Aon et al., 2007a, Gustafsson and Gottlieb, 2008, Slodzinski et al., 2008). Thus, maintaining Δψm is of paramount importance. Oxidative stress is a major pathophysiological route to the collapse of Δψm (Aon et al., 2003, Aon et al., 2004, Brady et al., 2004, Zorov et al., 2000). The toxic effects of ROS are kept in check throughout our lives by balancing the natural rates of ROS production with sophisticated antioxidant defense systems. If this balance between ROS production and ROS scavenging is disrupted, serious and often irreversible cell damage occurs (Halliwell, 1997). One such important pathological situation in the heart is reperfusion following ischemia, when ROS production accelerates and the detoxification systems are overwhelmed, resulting in the consumption of antioxidants and an increase in free radical concentrations (Aon et al., 2007a, Lucas and Szweda, 1998, Marczin et al., 2003, Slodzinski et al., 2008). This is the period during which Δψm is most likely to become unstable, representing a major decision point between cell life or death.

Section snippets

Mitochondrial physiology and ion channels

The oxidation of fuels (e.g., fatty acids and glucose) leads to acetyl-CoA, the common substrate for the Krebs cycle which, in turn, drives the production of the reducing equivalents NADH and FADH2. Electrons are passed to the electron transport chain, where coupled redox reactions mediate proton translocation across the inner membrane to establish a proton-motive force (PMF) composed of an electrical potential and pH gradient that drives ATP synthesis by the mitochondrial ATP synthase. The PMF

The ROS-dependent mitochondrial oscillator

When mitochondria oscillate in living cells, the asymmetry of the Δψm depolarization–repolarization cycle is consistent with the behavior exhibited by relaxation oscillators that possess slow and fast components (Cortassa et al., 2004). The sudden, fast, depolarization phase of Δψm during the oscillations suggested that an energy dissipating ion channel is opening, causing rapid uncoupling of oxidative phosphorylation.

An obvious candidate for rapid depolarization of Δψm was the PTP, which can

Mitochondrial network function

Mitochondria constitute an extensive subcellular network within the myocardial syncytium (Fig. 1). Pathological conditions induce synchronized, coupled oscillations across the mitochondrial network of the cardiac myocyte (Aon et al., 2003) or the whole heart (Slodzinski et al., 2008). That the cardiac mitochondrial network may be organized as a network of coupled oscillators in the physiological regime was inspired by a model prediction that anticipated the existence of the high-frequency

The importance of preserving Δψm: the role of mitochondrial inner membrane ion channels, redox potential and ROS

Previous results showed that oxidative stress can trigger the collapse of Δψm followed by cell-wide oscillations in isolated cardiomyocytes (Aon et al., 2003) or in whole hearts (Slodzinski et al., 2008). These oscillations in Δψm drive changes in the action potential (AP) through activation of the sarcolemmal KATP channel in response to rapid uncoupling of oxidative phosphorylation during depolarization of Δψm. Activation of sarcolemmal KATP currents shortens the cellular AP and renders the

Synchronized mitochondrial oscillations drive the sarcolemmal action potential

Early studies showed that cardiomyocytes subjected to energetic stress by substrate deprivation display spontaneous oscillations (period ∼1–3 min) in sarcolemmal currents that were attributed to the cyclical activation and deactivation of ATP-sensitive potassium current (IK,ATP) (O’Rourke et al., 1994). Since the period and amplitude of the IK,ATP oscillations were the same in electrically stimulated or quiescent cells, a Ca2+ – or plasma membrane potential – dependent source of oscillation was

The mitochondrial origin of post-ischemic arrhythmias

After ischemic injury, the early reperfusion phase would be expected to favor mitochondrial criticality since a burst of ROS production and antioxidant depletion are known to occur (Bolli and Marban, 1999, Slodzinski et al., 2008). Optical mapping studies of isolated perfused guinea pig hearts subjected to 30 min of ischemia demonstrated that persistent ventricular tachycardia and/or fibrillation occurs within minutes of reperfusion (Akar et al., 2005). In this experimental system we determined

Metabolic sink/block as a mechanism of conduction failure and arrhythmias

The results described in the previous section support the idea that “metabolic sinks” develop during I/R, and that this pattern is related to individual cells experiencing high levels of oxidative stress.

The Δψm loss occurring on reperfusion when coupled with activation of sarcolemmal KATP channels may create spatial and temporal AP heterogeneity that can be a substrate of ventricular reentry (Akar et al., 2005). Within this rationale we postulated that the failure of mitochondrial energetics

Final remarks: escalation of failures from the mitochondrial network to the whole heart

A central insight derived from the Complex Systems Approach (Aon and Cortassa, 2009) has been to show that complex systems, including physical, social, economic, or biological networks, can collapse, crash, or rupture when stressed (Sornette, 2000). The mitochondrial network of cardiac cells is no exception. Fig. 6 shows the sequence of events, from the mitochondrion to the whole organ, leading to arrhythmias. Under oxidative stress mitochondria accumulate high levels of ROS that – when the

Acknowledgement

This work was supported by NIH grants R37-HL54598, R33-HL87345 and P01-HL081427(BO’R).

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