Proton leak regulates mitochondrial reactive oxygen species generation in endothelial cell activation and inflammation - A novel concept

Abstract

Mitochondria are capable of detecting cellular insults and orchestrating inflammatory responses. Mitochondrial reactive oxygen species (mtROS) are intermediates that trigger inflammatory signaling cascades in response to our newly proposed conditional damage associated molecular patterns (DAMP). We recently reported that increased proton leak regulates mtROS generation and thereby exert physiological and pathological activation of endothelial cells. Herein, we report the recent progress in determining the roles of proton leak in regulating mtROS, and highlight several important findings: 1) The majority of mtROS are generated in the complexes I and III of electron transport chain (ETC); 2) Inducible proton leak and mtROS production are mutually regulated; 3) ATP synthase-uncoupled ETC activity and mtROS regulate both physiologica006C and pathological endothelial cell activation and inflammation initiation; 4) Mitochondrial Ca 2+ uniporter and exchanger proteins have an impact on proton leak and mtROS generation; 5) MtROS connect signaling pathways between conditional DAMP-regulated immunometabolism and histone post-translational modifications (PTM) and gene expression. Continuous improvement of our understanding in this aspect of mitochondrial function would provide novel insights and generate novel therapeutic targets for the treatment of sterile inflammatory disorders such as metabolic diseases, cardiovascular diseases and cancers.

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

“…However, mitochondrial oxidants can induce phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), resulting in activation of the receptor and subsequent angiogenesis. Similar to those findings, our previous reports showed that i) IL-35 inhibits lipopolysaccharide (LPS) and proatherogenic lipids LPC induced HAEC activation ( 5 , 7 ); ii) IL-35 suppresses vascular inflammation and atherosclerosis via inhibiting mitochondrial ROS( 8 , 9 , 34 – 37 ); iii) hypoxia may induce thrombus leukocyte transdifferentiation by upregulating endothelial cell-specific angiogenic markers ( 38 ); and iv) inhibition of caspase-1/inflammasome activation in EC improves ischemia-triggered angiogenesis ( 39 , 40 ). However, the question remained whether IL-35 modulates ischemia-triggered angiogenesis potentially via a ROS-related mechanism.…”

Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD)

“…However, the extent of ROS produced by mtETC may increase during mtETC malfunctions. These extra ROS are mainly produced by the I and III complexes of mtETC in coupling with induced proton leak [45]. A small imbalance in mtETC functions may lead to a transient accumulation of ROS, which could damage mtDNA in genes encoding mtETC components.…”

Approaching Inflammation Paradoxes—Proinflammatory Cytokine Blockages Induce Inflammatory Regulators

“…In addition, CVDs, cancers, and autoimmune diseases all share a common feature of increased mtROS levels (72). Our recent study shed light on this important question and found that, during endothelial cell activation, mtROS could be upregulated in a proton leak-coupled, but ATP synthesis-uncoupled manner (72)(73)(74)(75). As a result, endothelial cells could upregulate mtROS production for physiological endothelial cell activation without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and endothelial cell death.…”

“…As a result, endothelial cells could upregulate mtROS production for physiological endothelial cell activation without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and endothelial cell death. Thus, a novel pathophysiological role of proton leak in driving mtROS production was uncovered for lowgrade endothelial cell activation, patrolling immunosurveillance cell trans-endothelial migration and low-grade chronic inflammation without compromising cellular survival (72)(73)(74)(75)(76). One of the most evident features of the inflammatory response is the generation of a pro-oxidative environment due to the production of high fluxes of pro-oxidant species (77).…”