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

Abstract

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 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 to 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 physiological 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/death. Mapping the connections between mitochondrial metabolism, physiological EC activation, patrolling cell migration and pathological inflammation is significant towards the development of novel therapies for inflammatory diseases and cancers.

Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases

“…Our data implies that inhibition of mitochondrial ROS generation can significantly reduce the atherosclerotic burden in aortas of hyperlipidemic mice. Therefore, the major purpose for LPC-mediated increase in proton leak may be to modulate the mitochondrial ROS generation for signal transduction that ultimately lead to endothelial cell activation, without inducing mitochondrial damage or endothelial cell death [47, 49]. …”

RETRACTED ARTICLE: Astragalus polysaccharide alleviates H 2 O 2 -triggered oxidative injury in human umbilical vein endothelial cells via promoting KLF2

“…The damage of vascular endothelial cells induced by oxidative stress is chiefly adjusted via reactive oxygen species (ROS). ROS can regulate the concentration of calcium ion in cytoplasm and the production of nitric oxide (NO), weaken vasodilation and lead to vascular endothelial damage [7]. Therefore, how to alleviate oxidative stress injury of endothelial cells is the key means to prevent and treat various vascular dysfunction-related diseases.…”

Mitochondrial dysfunction is implicated in retinoic acid‐induced spina bifida aperta in rat fetuses

“…Therefore, we analyzed the correlation between oxidative stress and mitochondrial dysfunction. As explained in a prior review (Li et al, 2017), mtROS generation mainly takes place in the electron transport chain located on the inner mitochondrial membrane during oxidative phosphorylation. As mitochondria are both sources and targets of ROS, amplification of oxidative damage can occur in the mitochondria because increased ROS can damage mitochondria and further exacerbate ROS production.…”

“…Our study demonstrated that the proportion of mitochondrial respiration coupled to ATP production was decreased, while proton leak was increased. A recent study revealed that, during endothelial cell activation, mtROS are upregulated in a proton leak‐coupled manner (Li et al, 2017). Thus, the novel pathophysiological role of proton leak in driving mtROS production explains how mtROS could be generated independently from ATP synthesis and endothelial damage/death.…”