A Reaction-Diffusion Model of ROS-Induced ROS Release in a Mitochondrial Network

Loss of mitochondrial function is a fundamental determinant of cell injury and death. In heart cells under metabolic stress, we have previously described how the abrupt collapse or oscillation of the mitochondrial energy state is synchronized across the mitochondrial network by local interactions dependent upon reactive oxygen species (ROS). Here, we develop a mathematical model of ROS-induced ROS release (RIRR) based on reaction-diffusion (RD-RIRR) in one- and two-dimensional mitochondrial networks. The nodes of the RD-RIRR network are comprised of models of individual mitochondria that include a mechanism of ROS-dependent oscillation based on the interplay between ROS production, transport, and scavenging; and incorporating the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and Ca2+ handling. Local mitochondrial interaction is mediated by superoxide (O2.−) diffusion and the O2.−-dependent activation of an inner membrane anion channel (IMAC). In a 2D network composed of 500 mitochondria, model simulations reveal ΔΨm depolarization waves similar to those observed when isolated guinea pig cardiomyocytes are subjected to a localized laser-flash or antioxidant depletion. The sensitivity of the propagation rate of the depolarization wave to O2.− diffusion, production, and scavenging in the reaction-diffusion model is similar to that observed experimentally. In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that ΔΨm depolarization is mediated specifically by O2.−. The present work demonstrates that the observed emergent macroscopic properties of the mitochondrial network can be reproduced in a reaction-diffusion model of RIRR. Moreover, the findings have uncovered a novel aspect of the synchronization mechanism, which is that clusters of mitochondria that are oscillating can entrain mitochondria that would otherwise display stable dynamics. The work identifies the fundamental mechanisms leading from the failure of individual organelles to the whole cell, thus it has important implications for understanding cell death during the progression of heart disease

Autocrine motility-stimulatory pathways of oral premalignant lesion cells

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity

Mitochondrial Reactive Oxygen Species (ROS) and Arrhythmias.

In this chapter we analyze the onset of cardiac arrhythmias from the perspective of mitochondrial redox state and energetic metabolism. Significant perturbations in the mitochondrial redox environment trigger mitochondrial membrane potential (ΔΨm) depolarization that under critical conditions can scale up to the whole heart, thereby producing fatal arrhythmias. Utilizing a combined experimental–theoretical approach, we evaluate the processes dynamics at each level of organization involved (molecular, mitochondrial, cardiomyocyte, whole heart) while highlighting their mechanistic interrelationships to explain the appearance of novel emergent properties. Under metabolically stressful conditions, the mitochondrial network of cardiac cells accumulate high level of reactive oxygen species (ROS) attaining a critical state – referred to as mitochondrial criticality. Under criticality, the slightest perturbation triggers a cell-wide collapse of ΔΨm, visualized as a depolarization wave throughout the cell, which is followed by whole cell sustained mitochondrial oscillations in ΔΨm, NADH, ROS, and glutathione. This macroscopic dynamic behavior escalates from the mitochondrion to the organ level driving the heart into catastrophic arrhythmias.Fil: Kembro, Jackelyn Melissa. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Cortassa, Sonia del Carme. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Aon, Miguel A.. University Johns Hopkins; Estados Unido