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Can J Physiol Pharmacol. 2017 Mar;95(3):247-252. doi: 10.1139/cjpp-2016-0515. Epub 2016 Nov 5.

Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells.

Li X1,1, Fang P1,1, Yang WY1,1, Chan K1,1, Lavallee M1,1, Xu K1,1, Gao T1,1, Wang H1,1, Yang X1,1.

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Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.


Mitochondrial reactive oxygen species (mtROS) are signaling molecules, which drive inflammatory cytokine production and T cell activation. In addition, cardiovascular diseases, cancers, and autoimmune diseases all share a common feature of increased mtROS level. Both mtROS and ATP are produced as a result of electron transport chain activity, but it remains enigmatic whether mtROS could be generated independently from ATP synthesis. A recent study shed light on this important question and found that, during endothelial cell (EC) activation, mtROS could be upregulated in a proton leak-coupled, but ATP synthesis-uncoupled manner. As a result, EC could upregulate mtROS production for physiological EC activation without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and EC death. Thus, a novel pathophysiological role of proton leak in driving mtROS production was uncovered for low grade EC activation, patrolling immunosurveillance cell trans-endothelial migration and other signaling events without compromising cellular survival. This new working model explains how mtROS could be increasingly generated independently from ATP synthesis and endothelial damage or death. Mapping the connections among mitochondrial metabolism, physiological EC activation, patrolling cell migration, and pathological inflammation is significant towards the development of novel therapies for inflammatory diseases and cancers.


ROS; cancer; cardiovascular disease; dérivés réactifs de l’oxygène; inflammation vasculaire; maladies cardiovasculaires; mitochondria; mitochondrie; vascular inflammation

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