Proton leak regulates mitochondrial reactive oxygen species generation in endothelial cell activation and
Gayani K Nanayakkara1, Hong Wang1, Xiaofeng Yang1
1Centers for Metabolic Disease Research, Cardiovascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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 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.
Insights
Mitochondria detect cellular damage and trigger inflammation via mitochondrial reactive oxygen species (mtROS). Proton leak regulates mtROS, influencing endothelial cell activation and inflammatory responses in sterile diseases.
Area of Science:
- Mitochondrial biology
- Cellular signaling
- Immunometabolism
Background:
- Mitochondria detect cellular insults and orchestrate inflammatory responses.
- Mitochondrial reactive oxygen species (mtROS) act as signaling intermediates.
- Conditional damage-associated molecular patterns (DAMPs) trigger inflammatory cascades.
Purpose of the Study:
- To elucidate the role of proton leak in regulating mtROS generation.
- To highlight key findings on the interplay between proton leak, mtROS, and cellular activation.
- To explore the connection between mtROS and immunometabolism in gene expression.
Main Methods:
- Investigating electron transport chain (ETC) complex activity.
- Analyzing the regulation of inducible proton leak and mtROS production.
- Examining the impact of mitochondrial ion transport proteins on mtROS.
- Assessing the role of mtROS in endothelial cell activation and inflammation.
Main Results:
- Most mtROS are generated in ETC complexes I and III.
- Inducible proton leak and mtROS production exhibit mutual regulation.
- ATP synthase uncoupling, mtROS, and endothelial cell activation are interconnected.
- Mitochondrial Ca2+ transporters influence proton leak and mtROS.
- MtROS link DAMP signaling, immunometabolism, histone PTMs, and gene expression.
Conclusions:
- Proton leak is a critical regulator of mtROS and cellular inflammatory responses.
- Understanding these pathways offers therapeutic targets for sterile inflammatory disorders.
- Further research can advance treatments for metabolic diseases, cardiovascular diseases, and cancers.
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