Functional Role of Mitochondria in Arrhythmogenesis

Abstract

Growing evidence indicate that mitochondria play a functional role in arrhythmogenesis. We report here the molecular mechanisms underlying the action of these highly dynamic organelles in the regulation of cell metabolism, action potential and, overall, heart excitability. In particular, we examine the role of cardiac mitochondria in linking metabolism and cell excitability. The importance of the main mitochondrial channels is evaluated as well, including the recently identified calcium uniporter. Promises and pitfalls of potential therapeutic strategies targeting mitochondrial pathways are also assessed.

Fig. 10.1

Role of sarcKATP channels in linking cell metabolic status and cell excitability. Mitochondrial dysfunction lead to increase of ROS and reduction of mitochondrial potential with consequent decrease of ATP production. ATP decrease, ATP and Pi activate sarcKATP channel, with K dissipating current and reduction of AP that predispose to arrhythmia

Fig. 10.2

TSPO regulates mitochondrial dissipating energy channel. In presence of low levels of ROS, TSPO is able to activate IMAC with consequent RIRR response that can induce arrhythmia. In presence of high levels of ROS, TSPO becomes able to activate mPTP with terminal collapse of mitochondrial potential and cell death

Fig. 10.3

Ca²⁺ dependent pathways and mitochondrial function in arrhythmogenesis. Alterations of Ca²⁺ release from sarcoplasmic reticulum can induce mitochondrial dysfunction as consequence of mitochondrial Ca²⁺ overload. Mitochondrial dysfunction in turn, through means of oxidative stress, can mediate further alterations with increase of Ca²⁺ leak from SR