Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 662, Issue -, Pages 68-74Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2018.12.002
Keywords
Proton leak; Mitochondrial reactive oxygen species (mtROS); Endothelial cell activation; Electron transport chain (ETC) uncoupling; Cardiovascular diseases
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Funding
- NIH [RO1 - HL132399-01A1]
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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 physiological and pathological endothelial cell activation and inflammation initiation; 4) Mitochondrial Ca2+ 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.
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