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

Polarization of the mitochondrial membrane potential (Delta Psi(m)) is critical for normal mitochondrial function and cellular energetics. Mitochondrial dysfunction, manifesting as disrupted Delta Psi(m) polarization (i.e. depolarization or hyperpolarization), underlies several important and highly prevalent diseases, including a variety of cardiac and neurological disorders. As such, Delta Psi(m) instability might form a unifying mechanism for a class of metabolic disorders affecting excitable tissues. Here, we measured the spatio-temporal kinetics of Delta Psi(m), changes across the intact heart using high-resolution optical Delta Psi(m) imaging and uncovered surprisingly complex spatial patterns and dynamically fluctuating changes in Delta Psi(m) that developed into actively propagating waves of mitochondrial depolarization during global ischemia. Our data further indicated that the recovery of Delta Psi(m) upon reperfusion is dictated by the duration of the preceding ischemic insult. Post-ischemic electrical and functional recovery was dependent on early Delta Psi(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. (c) 2010 Elsevier Ltd. All rights reserved.