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Reactive oxygen species (ROS) and/or Ca²⁺ overload can trigger depolarization of mitochondrial inner membrane potential (ΔΨ_m) and cell injury. Little is known about how loss of ΔΨ_m in a small number of mitochondria might influence the overall function of the cell. Here we employ the narrow focal excitation volume of the two-photon microscope to examine the effect of local mitochondrial depolarization in guinea pig ventricular myocytes. Remarkably, a single local laser flash triggered synchronized and self-sustained oscillations in ΔΨ_m, NADH, and ROS after a delay of ∼40s, in more than 70% of the mitochondrial population. Oscillations were initiated only after a specific threshold level of mitochondrially produced ROS was exceeded, and did not involve the classical permeability transition pore or intracellular Ca²⁺ overload. The synchronized transitions were abolished by several respiratory inhibitors or a …