Relating Mitochondrial Flickering to Whole-Cell Oscillations in Cardiac Mitochondrial Networks

Abstract

The membrane potential of individual mitochondria has been shown to “flicker” randomly, in conjunction with the release of reactive oxidative species (ROS), such as superoxide flashes demonstrated recently in experiments. Under conditions of laser-induced oxidative stress, mitochondrial depolarization waves and oscillations, attributed to ROS-induced ROS release (RIRR) have been observed in cardiac myocytes and simulated in computer models. However, how asynchronous single mitochondrial flickering transitions to organized mitochondrial waves and oscillations is unknown. In this study, we developed a simplified, agent-based model of mitochondrial networks. In a single mitochondrion, superoxide production was modeled as a bistable process, where low oxygen triggers a higher percentage of oxygen shunted to superoxide. Mitochondrial channels (IMAC and mPTP) open stochastically in response to superoxide inside the matrix and cytoplasm (RIRR), causing flickering in the membrane potential and release of superoxide into the cytoplasm. In a globally coupled network simulating a well-mixed population of isolated mitochondria in a cuvette, we recapitulated experimental findings from isolated heart mitochondria showing that membrane potential oscillated when oxygen reached a critically low level. The oscillations were a self-organizing behavior arising from synchronization of flickering mitochondria at low oxygen levels. Using the same mitochondrial model in a locally coupled network to simulate the mitochondrial network of a myocyte, we found that the frequency of randomly flickering increased as ROS levels increased. At a critical level, a phase transition occurred in which self-organizing clusters of depolarized mitochondria propagated through the network, resulting in ROS waves and whole-cell oscillations. Our model predicts that this phase transition can be induced through either excessive laser light or hypoxic conditions.