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Mitochondria have long been recognized for their importance in energy production and apoptosis. More recently, seminal work in various laboratories has extended the role of cardiac mitochondria from relatively static arbitrators of cell death and survival pathways to highly dynamic organelles that formed interactive networks across cardiomyocytes. These coupled networks were shown to strongly affect cardiomyocyte responses to oxidative stress by modulating key cell signaling pathways that strongly impacted physiological properties (Dedkova and Blatter, 2008; Aon, 2010; O'Rourke, 2010). Of particular importance is the role of mitochondria in storing and releasing intracellular calcium, which in turn, modulates excitation–contraction coupling and electrophysiological properties either directly or indirectly by affecting cell signaling cascades and ATP levels (Dedkova and Blatter, 2008). This important recognition has ushered a renewed interest in understanding, at a more fundamental level, the exact role that cardiac metabolism, in general and mitochondria, in particular, play in both health and disease. As a result, the journal “Frontiers in Mitochondrial Physiology” was born (Aon, 2010; O'Rourke, 2010).  O'Rourke and colleagues demonstrated that mitochondria formed networks of weakly coupled oscillators that spanned the entire cardiomyocyte (Aon et al., 2003). Upon reaching a critical level of oxidative stress, these networks exhibited emergent behavior that rapidly led to synchronized cell wide oscillations of the mitochondrial membrane potential, a key metric of mitochondrial function, and ATP production (Aon et al., 2003). This, in turn, resulted in cyclical oscillations of the cellular action potential via activation of the surface K-ATP current. Furthermore, spatially heterogeneous areas in tissue excitability during conditions that promoted mitochondrial membrane potential collapse led to the formation of conduction block via a mechanism which was termed metabolic sink (Akar et al., 2005; Aon, 2010). This form of conduction failure caused the genesis of sustained arrhythmias upon reperfusion (Akar et al., 2005; Aon, 2010).  In this issue of the Journal, Florea and Blatter demonstrate yet another mechanism by which mitochondrial membrane potential depolarization may lead to the genesis of arrhythmias, this time through a completely distinct mechanism that involves the formation of a beat-to-beat oscillatory behavior of the intracellular calcium transient. Using a highly systematic approach, these authors nicely demonstrated how disruption of mitochondrial energetics at various levels within the electron transport chain always led to a predictable increase in calcium transient alternans during steady state pacing of atrial myocytes. As such, these findings assigned another important role for cardiac mitochondria as mediators of a pathophysiological parameter (alternans) known to foreshadow the genesis of sudden death.

Mitochondrial Dysfunction: A New Frontier in the Search for Elusive Arrhythmia Mechanisms