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 spatiotemporal 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. Postischemic 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.

Strategic localization of heart mitochondrial NOS: a review of the evidence

“…At NO levels such as those reached during ischemia-reperfusion of cardiomyocytes, a reduction of ⌬ is produced with the subsequent reduction of Ca 2ϩ accumulation, thus protecting the cells from potentially lethal mitochondrial Ca 2ϩ overload (88,113). The cell injury and death observed after reoxygenation of the tissue are in accordance with several reports showing that NO can prevent or accelerate mPTP (31).…”

Mitochondrial depolarization and asystole in the globally ischemic rabbit heart: coordinated response to interventions affecting energy balance

“…The effects of blebbistatin were fully abolished by the inhibitor of glycolysis iodoacetate, suggesting energy preservation as the underlying mechanism. Importantly, even in the absence of blebbistatin, a significant ⌬⌿ m depolarization occurred relatively late (at ϳ25 min of ischemia), which is much later than it was previously thought (14) and suggests that ⌬⌿ m has little or no role in early ischemic events, such as contraction failure, action potential shortening (2), and action potential alternans (25). However, under all tested conditions, there was a direct correlation between t asys and t mito_depol , which is compatible with a causal relationship between the two events, although it may also indicate a mutual dependence on a critical level of energy depletion.…”

“…Assuming that this method faithfully reproduces the actual ⌬⌿ m loss during ischemia, we have to conclude that a significant ⌬⌿ m depolarization occurs relatively late (at ϳ25 min of ischemia). This is much later than it was previously thought (14) and suggests that ⌬⌿ m depolarization has little or no role in early ischemic events, such as contraction failure, action potential shortening (2), and action potential alternans (25). It is of interest that the observed timing of ⌬⌿ m loss is close to the minimal duration of ischemia in the rabbit heart after which myocardial infarction is detectable (20 min) (15).…”

Exenatide Reduces Final Infarct Size in Patients With ST-Segment–Elevation Myocardial Infarction and Short-Duration of Ischemia

“…One such mechanism may be recovery of the mitochondrial membrane potential that is changed during ischemia and tends to recover after generation of flow. 36 The ability of the membrane potential to recover depends on the duration of preceding ischemia. 36 Furthermore, changes in the mitochondrial potential are related to the myocardial damage after ischemia-reperfusion.…”

“…36 The ability of the membrane potential to recover depends on the duration of preceding ischemia. 36 Furthermore, changes in the mitochondrial potential are related to the myocardial damage after ischemia-reperfusion. 37 Future experimental and larger clinical studies are needed to clarify the relationship between reperfusion injury and cardioprotection on one side and time to reperfusion/duration of ischemia on the other.…”