Linking flickering to waves and whole-cell oscillations in a mitochondrial network model

It has been shown that transient single mitochondrial depolarizations, known as flickers, tend to occur randomly in space and time. On the other hand, many studies have shown that mitochondrial depolarization waves and whole-cell oscillations occur under oxidative stress. How single mitochondrial flickering events and whole-cell oscillations are mechanistically linked remains unclear. In this study, we developed a Markov model of the inner membrane anion channel in which reactive-oxidative-species (ROS)-induced opening of the inner membrane anion channel causes transient mitochondrial depolarizations in a single mitochondrion that occur in a nonperiodic manner, simulating flickering. We then coupled the individual mitochondria into a network, in which flickers occur randomly and sparsely when a small number of mitochondria are in the state of high superoxide production. As the number of mitochondria in the high-superoxide-production state increases, short-lived or abortive waves due to ROS-induced ROS release coexist with flickers. When the number of mitochondria in the high-superoxide-production state reaches a critical number, recurring propagating waves are observed. The origins of the waves occur randomly in space and are self-organized as a consequence of random flickering and local synchronization. We show that at this critical state, the depolarization clusters exhibit a power-law distribution, a signature of self-organized criticality. In addition, the whole-cell mitochondrial membrane potential changes from exhibiting small random fluctuations to more periodic oscillations as the superoxide production rate increases. These simulation results may provide mechanistic insight into the transition from random mitochondrial flickering to the waves and whole-cell oscillations observed in many experimental studies.