Cited by 168Mitochondrial Function and PathologyCardiac Ischemia and ReperfusionATP Synthase and ATPases Research

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

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Cheng, Jiali, Nanayakkara, Gayani, Shao, Ying, Cueto, Ramon, Wang, Luqiao, Yang, William Y., Tian, Ye, Wang, Hong, Yang, Xiaofeng·2017·Advances in Experimental Medicine and Biology

DOI 10.1007/978-3-319-55330-6_20PMC PMC5630226

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Abstract

Mitochondrial proton leak is the principal mechanism that incompletely couples substrate oxygen to ATP generation. This chapter briefly addresses the recent progress made in understanding the role of proton leak in the pathogenesis of cardiovascular diseases. Majority of the proton conductance is mediated by uncoupling proteins (UCPs) located in the mitochondrial inner membrane. It is evident that the proton leak and reactive oxygen species (ROS) generated from electron transport chain (ETC) in mitochondria are linked to each other. Increased ROS production has been shown to induce proton conductance, and in return, increased proton conductance suppresses ROS production, suggesting the existence of a positive feedback loop that protects the biological systems from detrimental effects of augmented oxidative stress. There is mounting evidence attributing to proton leak and uncoupling proteins a crucial role in the pathogenesis of cardiovascular disease. We can surmise the role of "uncoupling" in cardiovascular disorders as follows; First, the magnitude of the proton leak and the mechanism involved in mediating the proton leak determine whether there is a protective effect against ischemia-reperfusion (IR) injury. Second, uncoupling by UCP2 preserves vascular function in diet-induced obese mice as well as in diabetes. Third, etiology determines whether the proton conductance is altered or not during hypertension. And fourth, proton leak regulates ATP synthesis-uncoupled mitochondrial ROS generation, which determines pathological activation of endothelial cells for recruitment of inflammatory cells. Continue effort in improving our understanding in the role of proton leak in the pathogenesis of cardiovascular and metabolic diseases would lead to identification of novel therapeutic targets for treatment.

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“It has been suggested that increased proton leak is directly related to the prevention of oxidative stress, the inhibition of fatty acid induced mitochondrial damage and the control of oxidative phosphorylation [25], potentially protecting the cell from excessive damage.”
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Authors: Cheng, J., Nanayakkara, G., Shao, Y., Cueto, R., Wang, L., Yang, W. Y., Tian, Y., Wang, H., & Yang, X.
Affiliations: Harbin Medical University (CN)
Temple University (US)
Corresponding author: Yang, Xiaofeng
ORCID: Cheng, Jiali
Shao, Ying
Wang, Luqiao
Yang, William Y.
Tian, Ye
Yang, Xiaofeng
Venue: Advances in Experimental Medicine and Biology
Publisher: Springer International Publishing
Published: 2017
Volume: 982
Pages: 359-370
ISSN: 0065-2598 (ISSN-L)
2214-8019
DOI: 10.1007/978-3-319-55330-6_20
PMC: PMC5630226
OpenAlex: W2617303046
Cited by: 168
References: 51
Citations by year: 2026: 6 · 2025: 22 · 2024: 18 · 2023: 29 · 2022: 25 · 2021: 16 · 2020: 29 · 2019: 8 · 2018: 13 · 2017: 2
FWCI: 17.73
Type: book chapter
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (unspecified)
Locations: Advances in experimental medicine and biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL117654, R01HL138749, R01HL131460, R01HL132399)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113775, R01DK104116)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Keywords: mitochondrial proton leak, uncoupling proteins, uncoupling, reactive oxygen species, electron transport chain, oxidative stress, ischemia-reperfusion injury, UCP2, vascular function, obesity, diabetes mellitus, hypertension, endothelial activation, inflammation, ATP production, cardiovascular disease pathogenesis
MeSH terms: Adenosine Triphosphate, Animals, Cardiovascular Diseases, Electron Transport, Energy Metabolism, Humans, Mitochondria, Heart, Protons, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Myocytes, Cardiac, Electron Transport Chain Complex Proteins, Membrane Potential, Mitochondrial

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

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