Mitochondrial ROS versus ER ROS: Which Comes First in Myocardial Calcium Dysregulation?

Cardiomyocyte excitation–contraction coupling is tightly regulated through coordinated calcium release and uptake that is facilitated by two proteins in the sarco/endoplasmic reticulum (SR/ER) membrane, the ryanodine receptor (Ryr), and the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), respectively. Dysregulated calcium handling is a hallmark in cardiac dysfunction (1–3). Our understanding of the molecular mechanisms that underlie these calcium handling anomalies and their precise role in the associated pathologies remains incomplete. A growing body of indirect evidence has implicated a role for redox signaling, and the mitochondria have been thought to be the primary source of reactive oxygen species (ROS) (4–10). Research in this area suggests that ROS generated from the mitochondria alters the redox milieu around the SR/ER–mitochondria interface causing excessive oxidation of the cysteine residues in Ryr and SERCA that results in an increase in calcium release and decrease in uptake, respectively, thus depleting the SR/ER Ca2+ stores and causing dysregulated downstream signaling (4–10). However, many questions remain unanswered, and the source of the ROS has not been directly validated. Mitochondria and SR/ER are in close apposition and the interface, commonly known as the mitochondrial-associated ER membrane (MAM), is believed to act as the focal point for this signaling. Our knowledge of calcium signaling in cardiac pathologies, where ER and oxidative stresses are predominant (11–14), suggests that calcium may, in fact, be the cause, rather than the effect, of mitochondrial ROS. This implies that calcium overload signals mitochondria to produce lethal levels of ROS. Therefore, do alternative sources of ROS initiate the redox imbalance that causes calcium dysregulation? In this article, we present data that suggest that, in addition to mitochondrial ROS, ROS originating in the ER may indeed explain gaps existent in the field cardiovascular pathophysiology.