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


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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    • "One obvious reason is that mitochondria are the main site of lipid degradation. However, the major driving force underlying this association is the fundamental role played by mitochondrial dysfunction in aging and acute or chronic disease conditions such as metabolic disorders (obesity, diabetes), cancer, inflammatory disorders, neurodegeneration, and cardiovascular disease (Akar et al., 2005; Aon et al., 2009; Bugger and Abel, 2010; Camara et al., 2011; Martinez-Outschoorn et al., 2012; Wallace, 2012; Helguera et al., 2013; Cortassa et al., 2014; Rossignol and Frye, 2014). "
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    ABSTRACT: Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.
    Frontiers in Physiology 07/2014; 5:282. DOI:10.3389/fphys.2014.00282 · 3.53 Impact Factor
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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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    ABSTRACT: Background: Mitochondrial permeability transition pore (mPTP) opening is a terminal event leading to mitochondrial dysfunction and cell death under conditions of oxidative stress (OS). However, mPTP blockade with cyclosporine A (CsA) has shown variable efficacy in limiting post-ischemic dysfunction and arrhythmias. We hypothesized that strong feedback between energy dissipating (mPTP) and cardioprotective (mKATP) channels determine vulnerability to OS. Methods and results: Guinea pig hearts (N = 61) were challenged with H2O2 (200 μM) to elicit mitochondrial membrane potential (ΔΨm) depolarization. High-resolution optical mapping was used to measure ΔΨm or action potentials (AP) across the intact heart. Hearts were treated with CsA (0.1 μM) under conditions that altered the activity of mKATP channels either directly or indirectly via its regulation by protein kinase C. mPTP blockade with CsA markedly blunted (P < 0.01) OS-induced ΔΨm depolarization and delayed loss of LV pressure (LVP), but did not affect arrhythmia propensity. Surprisingly, prevention of mKATP activation with the chemical phosphatase BDM reversed the protective effect of CsA, paradoxically exacerbating OS-induced ΔΨm depolarization and accelerating arrhythmia onset in CsA treated compared to untreated hearts (P < 0.05). To elucidate the putative molecular mechanisms, mPTP inhibition by CsA was tested during conditions of selective PKC inhibition or direct mKATP channel activation or blockade. Similar to BDM, the specific PKC inhibitor, CHE (10 μM) did not alter OS-induced ΔΨm depolarization directly. However, it completely abrogated CsA-mediated protection against OS. Direct pharmacological blockade of mKATP, a mitochondrial target of PKC signaling, equally abolished the protective effect of CsA on ΔΨm depolarization, whereas channel activation with 30 μM Diazoxide protected against ΔΨm depolarization (P < 0.0001). Conditions that prevented mKATP activation either directly or indirectly via PKC inhibition led to accelerated ΔΨm depolarization and early onset of VF in response to OS. Investigation of the electrophysiological substrate revealed accelerated APD shortening in response to OS in arrhythmia-prone hearts. Conclusions: Cardioprotection by CsA requires mKATP channel activation through a PKC-dependent pathway. Increasing mKATP activity during CsA administration is required for limiting OS-induced electrical dysfunction.
    Frontiers in Physiology 07/2014; 5:264. DOI:10.3389/fphys.2014.00264 · 3.53 Impact Factor
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    • "Nevertheless, with adequate numbers of sarcK ATP channels in the open state, cardiomyocytes can become hyperpolarized and rendered unexcitable [171]. This creates a current sink capable of slowing or blocking electrical propagation in the myocardium, promoting the development of cardiac arrhythmia [36] [172]. "
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    ABSTRACT: Mitochondria are essential to providing ATP thereby satisfying the energy demand of the incessant electrical activity and contractile action of cardiac muscle. Emerging evidence indicates that mitochondrial dysfunction can adversely impact cardiac electrical functioning by impairing the intracellular ion homeostasis and membrane excitability through reduced ATP production and excessive reactive oxidative species (ROS) generation, resulting in increased propensity to cardiac arrhythmias. In this review, the molecular mechanisms linking mitochondrial dysfunction to cardiac arrhythmias are discussed with an emphasis on the impact of increased mitochondrial ROS on the cardiac ion channels and transporters that are critical to maintaining normal electromechanical functioning of the cardiomyocytes. The potential of using mitochondria-targeted antioxidants as a novel anti-arrhythmia therapy is highlighted.
    Free Radical Biology and Medicine 04/2014; 71. DOI:10.1016/j.freeradbiomed.2014.03.033 · 5.74 Impact Factor
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