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

doi:10.1016/j.abb.2018.12.002

Archives of Biochemistry and Biophysics

Volume 662, 15 February 2019, Pages 68-74

https://doi.org/10.1016/j.abb.2018.12.002 Get rights and content

Highlights

•
The majority of mitochondrial reactive oxygen species are generated in the complexes I and III of electron transport chain.
•
Inducible proton leak and mtROS production are mutually regulated
•
Proton leak and mitocondrial reactive oxygen species regulate physiological and pathological endothelial cell activation .
•
Mitochondrial Ca²⁺ uniporter and exchanger proteins regulate proton leak and mitochondrial reactive oxygen species generation.
•
Mitochondrial reactive oxygen species mediate conditional DAMP regulated histone post-translational modifications.

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.

Section snippets

Introduction - mitochondria are “sentinel” organelles capable of detecting cellular insults and orchestrating inflammatory responses

Historically considered as merely cellular “powerhouses” that manufacture ATP and other metabolites, mitochondria are increasingly being recognized as “sentinel” organelles, which are capable of detecting cellular insults and orchestrating inflammatory responses [1]. Mitochondria are complex organelles, which contain their own DNA and are composed of a double membrane; outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). This double membrane gives rise to two compartments;

The majority of mitochondrial reactive oxygen species (mtROS) are generated in the complexes I and III of electron transport chain (ETC)

As an important part of cellular reactive oxygen species system [28], mtROS has been identified as an intermediate that trigger inflammatory signaling cascade in response to DAMP and PAMP [18,29,30]. Despite ROS (reactive oxygen species) being identified as a toxin for its high reactivity with lipids, proteins and nucleic acids, recent studies have suggested its important role in mediating physiological cellular signaling during homeostasis [1,31]. Mitochondria are a significant source of ROS

Inducible proton leak and mtROS production are mutually regulated

Lipid membranes show high conductance to protons; therefore, protons migrate to the matrix of the mitochondria across IMM independent of complex V. This process is termed as “proton leak”. During proton leak, energy is dissipated as heat instead of being used for ATP synthesis [39]. As proton leak depicts the protons that migrate into the matrix without producing ATP, it makes the coupling of substrate oxygen and ATP generation incomplete. However, proton leak is the principal, but not the only

ATP synthase-uncoupled ETC activity and mtROS regulate both physiological and pathological endothelial cell activation and inflammation initiation

Recently, our lab published the effects of conditional DAMP LPC on inducing endothelial cell activation [21]. Endothelial activation is the initial step of the inflammatory process that initiate the circulating immune cells to adhere and migrate across the endothelium that ultimately lead to progression of atherosclerosis. Recently, we proposed two types of endothelial activation: 1) Physiological endothelial cell activation, and 2) Pathological endothelial cell activation [74]. We described

Mitochondrial Ca²⁺ uniporter and exchanger proteins have an impact on proton leak and mtROS generation

LPC acts through G-protein coupled receptors (GPCR). Our data indicated that low dose of LPC treatment significantly induced cytosolic and mitochondrial Ca²⁺ influx. So far, Ca²⁺ is one of the most important intracellular messengers that was extensively studied in various pathologies. Myriad of proteins are known to change their conformation and charge due to Ca²⁺ binding, therefore, the intrusion and extrusion of Ca²⁺ are tightly controlled at a cost of high energy consumption [77]. Just like

MtROS connects signaling pathways between conditional DAMP regulated immunometabolism and histone post-translational modifications (PTM) and gene expression

Our data implied that increased Ca²⁺ in the cytosol and mitochondria are responsible for mtROS production, which in turn induce PTM of histones in the nucleus. We hypothesize that increased activity of ATP synthase uncoupled ETC activity that result due to augmented ion mediated proton leak is responsible for increased mtROS production. Despite the prevailing notion that increased proton leak mitigates mtROS production, there are reports that demonstrate increased mtROS production in the

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This work was supported by a NIH grant to XY (Grant No. RO1 - HL132399-01A1).

Acknowledgements

None.

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

Highlights

Abstract

Section snippets

Introduction - mitochondria are “sentinel” organelles capable of detecting cellular insults and orchestrating inflammatory responses

The majority of mitochondrial reactive oxygen species (mtROS) are generated in the complexes I and III of electron transport chain (ETC)

Inducible proton leak and mtROS production are mutually regulated

ATP synthase-uncoupled ETC activity and mtROS regulate both physiological and pathological endothelial cell activation and inflammation initiation

Mitochondrial Ca2+ uniporter and exchanger proteins have an impact on proton leak and mtROS generation

MtROS connects signaling pathways between conditional DAMP regulated immunometabolism and histone post-translational modifications (PTM) and gene expression

Conflicts of interest

Funding

Acknowledgements

Cell Calcium

Transl. Neurodegener.

Biochim. Biophys. Acta

Drug Discov. Today Ther. Strat.

Cell

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

Mitochondrion

Redox Biol

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Comp. Biochem. Physiol. B Biochem. Mol. Biol.

Biochim. Biophys. Acta

Cell Metabol.

Best Pract. Res. Clin. Endocrinol. Metabol.

J. Biol. Chem.

Cell

J. Biol. Chem.

Trends Biochem. Sci.

Free Radical Biol. Med.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

J. Biol. Chem.

Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers

J. Hematol. Oncol.

Mitochondrial-nuclear communications

Annu. Rev. Biochem.

DNA checkpoint and repair factors are nuclear sensors for intracellular organelle stresses-inflammations and cancers can have high genomic risks

Front. Physiol.

Mitochondrial dynamics, mitophagy and cardiovascular disease

J. Physiol.

Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies

Annu. Rev. Pharmacol. Toxicol.

Mitochondria, cholesterol and cancer cell metabolism

Clin. Transl. Med.

Inflammasomes are differentially expressed in cardiovascular and other tissues

Int. J. Immunopathol. Pharmacol.

DAMPs from cell death to new life

Front. Immunol.

Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis

Am. J. Respir. Crit. Care Med.

ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors

Science

IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction

Nat. Immunol.

Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Nature

TLR signalling augments macrophage bactericidal activity through mitochondrial ROS

Nature

A role for mitochondria in NLRP3 inflammasome activation

Nature

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

Mitochondrial Ca²⁺ uniporter and exchanger proteins have an impact on proton leak and mtROS generation