Article

From mitochondrial dynamics to arrhythmias. Int J Biochem Cell Biol

Johns Hopkins University, School of Medicine, Division of Cardiology, 720 Rutland Ave., 1059 Ross Bldg., Baltimore, MD 21205, USA.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 11/2009; 41(10):1940-8. DOI: 10.1016/j.biocel.2009.02.016
Source: PubMed

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, Delta psi(m), visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in Delta psi(m), 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 Delta psi(m) 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.

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    • "Activation of these normally dormant channels is thought to be protective as they act to preserve energy at a time of increased metabolic demand. However, increasing K efflux through these channels can induce rapid and heterogeneous action potential duration (APD) shortening and suppress myocyte excitability in a manner that predisposes to reentrant arrhythmias [12] [13] [39] [41]. Importantly, both metabolic and electrophysiological oscillations could be readily abolished by TSPO ligands, which functionally reduce cardiomyocyte ROS levels [18–20, 39, 42]. "
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    Full-text · Article · Jul 2014 · Frontiers in Physiology
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    • "ΔΨm instability can lead to inexcitability at the cellular level and conduction block and arrhythmias at the organ level, via a mechanism termed “metabolic sink” (Akar et al., 2005). Furthermore, pharmacological blockade of IMAC which blunted ΔΨm depolarization improved electrical and functional recovery of the heart following IR injury (Akar et al., 2005; Brown et al., 2008; Aon et al., 2009). That work, however, focused on relatively mild levels of OS produced by short episodes of IR injury. "
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