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

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Book cover Mitochondrial Dynamics in Cardiovascular Medicine

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 982))

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.

Gayani Nanayakkara, Ying Shao, Ramon Cueto, Luqiao Wang, contributed to this work equally.

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    Authors and Affiliations

    1. Department of Cardiovascular Medicine, The First Affiliate Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

      Jiali Cheng, William Y. Yang & Ye Tian

    2. Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA

      Jiali Cheng, Gayani Nanayakkara, Ying Shao, Ramon Cueto, Luqiao Wang, Hong Wang & Xiaofeng Yang MD, PhD, FAHA

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    1. Jiali Cheng
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    2. Gayani Nanayakkara
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    3. Ying Shao
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    9. Xiaofeng Yang MD, PhD, FAHA
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    Correspondence to Xiaofeng Yang MD, PhD, FAHA .

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    1. Dept. of Biomedical Advanced Sciences, Federico II University, Naples, Italy

      Gaetano Santulli

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    Cheng, J. et al. (2017). Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases. In: Santulli, G. (eds) Mitochondrial Dynamics in Cardiovascular Medicine. Advances in Experimental Medicine and Biology, vol 982. Springer, Cham. https://doi.org/10.1007/978-3-319-55330-6_20

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