Effects of regional mitochondrial depolarization on electrical propagation: Implications for arrhythmogenesis

Lufang Zhou, Soroosh Solhjoo, Brent Millare, Gernot Plank, M. Roselle Abraham, Sonia Cortassa, Natalia Trayanova, Brian O'Rourke

Research output: Contribution to journalArticle

Abstract

Background-Sudden cardiac death often involves arrhythmias triggered by metabolic stress. Loss of mitochondrial function is thought to contribute to the arrhythmogenic substrate, but how mitochondria contribute to uncoordinated electrical activity is poorly understood. It has been proposed that the formation of metabolic current sinks, caused by the nonuniform collapse of mitochondrial inner membrane potential (Δψm), contributes to re-entrant arrhythmias because Δψm depolarization is tightly coupled to the activation of sarcolemmal ATP-sensitive K+ channels, hastening action potential repolarization and shortening the refractory period. Methods and Results-Here, we use computational and experimental methods to investigate how Δψm instability can induce re-entrant arrhythmias. We develop the first tissue-level model of cardiac electrical propagation incorporating cellular electrophysiology, excitation-contraction coupling, mitochondrial energetics, and reactive oxygen species balance. Simulations show that re-entry and fibrillation can be initiated by regional Δψm loss because of the disparity of refractory periods inside and outside the metabolic sink. Computational results are compared with the effects of a metabolic sink generated experimentally by local perfusion of a mitochondrial uncoupler in a monolayer of cardiac myocytes. Conclusions-The results demonstrate that regional mitochondrial depolarization triggered by oxidative stress activates sarcolemmal ATP-sensitive K+ currents to form a metabolic sink. Consequent shortening of the action potential inside, but not outside, the sink increases the propensity for re-entry. Δψ m recovery during pacing can lead to novel mechanisms of ectopic activation. The findings highlight the importance of mitochondria as potential therapeutic targets for sudden death associated with cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)143-151
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume7
Issue number1
DOIs
StatePublished - Feb 2014

Keywords

  • Arrhythmias
  • Cardiac
  • KATP channels
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Effects of regional mitochondrial depolarization on electrical propagation: Implications for arrhythmogenesis'. Together they form a unique fingerprint.

  • Cite this