Optical imaging of mitochondrial function uncovers actively propagating waves of mitochondrial membrane potential collapse across intact heart

Abstract 

Polarization of the mitochondrial membrane potential (ΔΨ_m) is critical for normal mitochondrial function and cellular energetics. Mitochondrial dysfunction, manifesting as disrupted ΔΨ_m polarization (i.e. depolarization or hyperpolarization), underlies several important and highly prevalent diseases, including a variety of cardiac and neurological disorders. As such, ΔΨ_m instability might form a unifying mechanism for a class of metabolic disorders affecting excitable tissues. Here, we measured the spatio-temporal kinetics of ΔΨ_m changes across the intact heart using high-resolution optical ΔΨ_m imaging and uncovered surprisingly complex spatial patterns and dynamically fluctuating changes in ΔΨ_m that developed into actively propagating waves of mitochondrial depolarization during global ischemia. Our data further indicated that the recovery of ΔΨ_m upon reperfusion is dictated by the duration of the preceding ischemic insult. Post-ischemic electrical and functional recovery was dependent on early ΔΨ_m recovery but independent of overall cellular injury measured using a standard assay of lactate dehydrogenase release. These findings reveal a novel mechanism by which instabilities in cellular energetic properties that are independent of irreversible cellular injury can scale to the level of the intact organ via an organized process of active conduction involving the multi-cellular network. This highlights the importance of investigating cellular metabolic properties in the context of the intact organ.

Keywords: Mitochondria, Oxidative stress, Mitochondrial membrane potential, Energetics