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Mitochondrial Calcium Entry Induces Mitochondrial Reactive Oxygen Species Production by ATP Synthase‐uncoupled, But Proton Leak‐coupled Mechanism – A New System of How Atherogenic Stimuli Activate Aortic Endothelial Cells without Compromising Endothelial Cell Survival

Previously considered as toxic byproducts of cellular metabolism, it was recently discovered that mitochondrial reactive oxygen species (mtROS) are in fact signaling molecules, which drive inflammatory cytokine production and T cell activation. In addition, pathological conditions as diverse as cancer, autoimmune diseases, and cardiovascular diseases all share common feature of increased mtROS production above basal levels. MtROS are generated from the partial oxygen reduction in the electron transport chain and a number of factors have been linked to mtROS production, including mitochondrial calcium (Ca2+), mitochondrial membrane potential, and proton leak. However, since mtROS and ATP production are both coupled to electron transport chain activity, it is unclear whether mitochondrial ROS could be induced independently from ATP synthesis in the cell. By using Seahorse XF96 mitochondrial function analyzer and other molecular biology approaches, we found that during endothelial cell (EC) activation process induced by proatherogenic stimuli lysophosphatidylcholine (lysoPC), mitochondrial calcium entry mediates proton leak‐coupled, but ATP‐synthesis‐uncoupled mitochondrial respiratory chain acceleration and increased mtROS production. By doing this, EC could upregulate mtROS production without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and endothelial cell death. Thus, we uncovered a novel pathophysiological role of proton leak in fine‐tuning mtROS production for endothelial activation purpose without compromising endothelial cell survival. This new working model explains how mtROS could be increasingly generated independently from ATP synthesis. Our finding is significant towards the development of novel mitochondrial ROS‐modulating therapies to combat cardiovascular inflammatory diseases, atherosclerosis, autoimmune diseases and cancers.