Contents

πŸ“’ Yang 2014

Mitochondria and arrhythmias1

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Introduction

  • Over 90% of the cellular ATP consumed in the heart is produced by the mitochondria through oxidative phosphorylation (OXPHOS)
  • mitochondria account for ~30% of the volume of cardiac cells, forming a network surrounding sarcoplasmic reticulum (SR), myofilaments and t-tubules
  • mitochondria also generate reactive oxygen species (ROS) as a by-product and for signaling => preconditioning
  • excessive mitochondrial ROS production can impair cardiac excitability
    • post-translational redox modification of cysteine (S-glutathionylation, sulfhydration and S-nitrosation or tyrosine (nitration) residues
    • CaMKII, PKC, cSrc, NFΞΊB
  • Mitochondria can uptake and extrude Ca2+, as a calcium buffer
  • sarcolemmal ATP-sensitive potassium (sarcKATP) currents activated during depletion of ATP => current sink

Ionic basis of cardiac excitability and contractile function

  • Myocardial action potentials are generated by the sequential activation and inactivation of ion channels conducting depolarizing, Na+ and Ca2+, and repolarizing, K+, currents

Mitochondrial energetics and ROS production

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096785/bin/nihms584382f1.jpg

  • mitochondria are viewed as the major source of ROS in cardiomyocytes
  • complex II ROS generation is minor. Major players are I and III.
  • An excessive amount of ROS, including superoxide, H2O2, hydroxyl radicals (β€’OH), and peroxynitrite (ONOOβˆ’/ONOOH), can lead to detrimental reactions with cellular lipids and proteins
  • Increased mitochondrial ROS also reduce ATP production
    • superoxide can activate mitochondrial uncoupling proteins
    • oxidative damage to components of ETC

Interdependent regulation of mitochondrial and sarcolemmal cation homeostasis

Mitochondrial Ca2+

  • crucial for the regulation of energy production, mitochondrial morphology and cell death
  • promoting CAC, OXPHOS and ATP production
  • increase in ROS production
  • activating mitochondrial permeability transition pore (mPTP)
  • imported by mitochondrial Ca2+ uniporter (MCU), gene 109A (CCDC109A)
  • Other mechanisms
    • rapid mode of uptake (RaM)
    • ryanodine receptor 1 (Ryr1)
    • Ca2+-selective conductance (mCa1 and mCa2)
  • Ca2+ transport from ER/SR into mitochondria
  • SR-mitochondria communication has been implicated in ischemia-reperfusion injury [84] and cardiac arrhythmias
  • Ca efflux by mNCX, mitochondrial Ca2+/H+ antiporter and PTP
  • mitochondria do not act as a significant buffer of cytosolic Ca2+ under physiological conditions. With prolonged elevation of cytosolic Ca2+ levels, however, mitochondrial Ca2+ uptake can increase 10- to 1000-fold and begin to impact cellular Ca2+ dynamics significantly

Mitochondrial Na

  • regulated by Na+/H+ exchanger (NHE)-mediated Na+ extrusion and mNCX-mediated Na+ uptake
  • Sarcolemmal Na+ levels increase significantly in pathological conditions such as heart failure
    • widens the Na+ gradient across mitochondria, leading to greater driving force for mNCX to extrude Ca2+ from mitochondria, thereby resulting in decreased mitochondrial [Ca2+] and altered mitochondrial energetics

Mitochondrial K

  • Mitochondrial matrix volume is controlled by K+ fluxes
  • K+ influx is mediated by Ca2+-dependent (KCa) and ATP-dependent (mitoKATP) K+ channels
  • K+ efflux is conducted through a K+/H+ exchanger (KHE). KHE is activated with the expansion of mitochondrial volume, preventing excess matrix swelling
  • Mitochondrial Ca2+ overload can result in mitochondrial swelling through the activation of KCa/mitoKATP and the inhibition of KHE

Mitochondrial ROS and cardiac sodium channels

  • Upon increased oxidative stress, the slowly inactivating component of sodium current (late INa) is shown to be increased in cardiomyocytes, leading to prolongation of action potential duration (APD), early after depolarizations (EAD), increased Na+/Ca2+ exchange and subsequent cellular Ca2+ overload
  • peak Ina is reduced by activated PKC => reduced conduction velocity => arrythmia

Cellular redox state, mitochondria, and Ca2+ homeostasis

  • LCC RyR, SERCA, NCX, CaMKII, Ξ²-adrenergic receptors (Ξ²-AR), PKA and PKC
  • All these Ca2+ handling proteins contain thiol groups or methionines that are susceptible to the direct regulation by ROS or reducing agents.
  • impaired mitochondrial function, with depolarized mitochondrial membrane potential and ATP depletion, can lead to calcium transient alternans by affecting the capacity of the mitochondrial network to handle Ca2+ on a beat-to-beat basis

mitochondrial Ca2+ is a positive effector of OXPHOS

  • Increased Ca2+ stimulates TCA cycle and OXPHOS
  • Stimulation of nitric oxide synthase (NOS)
  • Cytochrome c-mediated ETC inhibition: increased Ca2+ can enhance cytochrome c dislocation
  • Cross-talk with K+ influx
  • This positive feed-forward loop consisting of Ca2+-induced ROS production, ROS-induced ROS release and ROS-induced Ca2+ overload

ROS, mitochondria and cardiac potassium channels

  • Ito (transient outward Kv)
  • IK (delayed rectifier Kv)
  • IK1 (inward rectifier)
  • IKATP
  • Increased ROS have been shown to reduce the expression of Kv currents
  • myocardial APD can be significantly shortened even with the opening of only 1% of the sarcKATP channels => current sink
  • The opening of mitoKATP channels before the onset of ischemia allows K+ influx in mitochondria => maintaining mito volume => preconditioning

Mitochondrial ROS and cardiac gap junction remodeling

  • connexin (Cx) 40, Cx43 and Cx45.
  • renin-angiotensin system (RAS) => increased myocardial oxidative stress and downregulate ventricular Cx43 => decreased conduction velocity

Conclusion

Reduced ATP synthesis and increased ROS production associated with mitochondrial dysfunction can lead to malfunction of various cellular mechanisms

  • reduced peak INa and downregulation of Cx43 => reduced conduction velocity => reentrant type arrhythmias
  • increases late INa and reduces repolarizing Kv currents => prolonged APD, EADs
  • Increase LCC & RyR, reduced SERCA => cytosolic Ca2+ overload => proarrhythmic DADs
  • depolarization of ΔΨm and the opening of sarcoKATP channels, creating a current sink

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096785/bin/nihms584382f2.jpg https://user-images.githubusercontent.com/40054455/86726262-fcdbaa00-c05c-11ea-9011-c5372486e12f.png

Reference


  1. Yang KC, Bonini MG, Dudley SC. Mitochondria and arrhythmias. Free Radic Biol Med. 2014;71:351-61. PMC4096785 ↩︎