![]() 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. ![]() 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. Majority of the proton conductance is mediated by uncoupling proteins (UCPs) located in the mitochondrial inner membrane. This chapter briefly addresses the recent progress made in understanding the role of proton leak in the pathogenesis of cardiovascular diseases. Mitochondrial proton leak is the principal mechanism that incompletely couples substrate oxygen to ATP generation. Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases.Ĭheng, Jiali Nanayakkara, Gayani Shao, Ying Cueto, Ramon Wang, Luqiao Yang, William Y Tian, Ye Wang, Hong Yang, Xiaofeng Finally, we emphasize the importance of proton and electron leak as therapeutic targets in body mass regulation and insulin secretion. We also highlight recent progress and challenges of assessing electron leak in the living cell. As the mechanisms of electron leak are crucial to understanding their physiological relevance, we summarize the mechanisms and topology of electron leak from complexes I and III in studies using isolated mitochondria. Exit of electrons prior to the reduction of oxygen to water at cytochrome c oxidase causes superoxide production. The second part of the chapter focuses on the electron leak that occurs in the mitochondrial electron transport chain. The physiological role of inducible leak through UCP1 in mammalian brown adipose tissue is heat production, whereas the roles of non-mammalian UCP1 and its paralogous proteins, in particular UCP2 and UCP3, are not yet resolved. The inducible leak through the ANT (adenine nucleotide translocase) and UCPs (uncoupling proteins) can be activated by fatty acids, superoxide or lipid peroxidation products. The basal proton leak is cell-type specific and correlates with metabolic rate. The basal leak is unregulated, and a major proportion can be attributed to mitochondrial anion carriers, whereas the proton leak through the lipid bilayer appears to be minor. In the first part of this chapter, we address the molecular nature of the basal and inducible proton leak pathways, and their physiological importance. Mitochondrial proton and electron leak have a major impact on mitochondrial coupling efficiency and production of reactive oxygen species. Jastroch, Martin Divakaruni, Ajit S Mookerjee, Shona Treberg, Jason R Brand, Martin D This finding suggests that mitoflash genesis is functionally and mechanistically integrated with mitochondrial energy metabolism. ![]() We conclude that nanodomain protons act as a novel, to our knowledge, trigger of mitoflashes in energized mitochondria. Based on a numerical simulation, we estimated a mean proton lifetime of 1.42Â ns and diffusion distance of 2.06Â nm in the matrix. However, charge-uncompensated proton transport, which depolarizes mitochondria, caused the opposite effect, and steady matrix acidification mildly inhibited mitoflashes. Both electroneutral H(+)/K(+) or H(+)/Na(+) antiport and matrix proton uncaging elicited immediate and robust mitoflash responses over a broad dynamic range in cardiomyocytes and HeLa cells. Using multiple biosensors and chemical probes as well as label-free autofluorescence, we found that the mitoflash reflects chemical and electrical excitation at the single-organelle level, comprising bursting superoxide production, oxidative redox shift, and matrix alkalinization as well as transient membrane depolarization. ![]() In this study, we aimed to further delineate the signal components of the mitoflash and determine the mitoflash trigger mechanism. However, which signal controls their ignition and how they are integrated with other mitochondrial signals and functions remain elusive. Wang, Xianhua Zhang, Xing Huang, Zhanglong Wu, Di Liu, Beibei Zhang, Rufeng Yin, Rongkang Hou, Tingting Jian, Chongshu Xu, Jiejia Zhao, Yan Wang, Yanru Gao, Feng Cheng, HepingĮmerging evidence indicates that mitochondrial flashes (mitoflashes) are highly conserved elemental mitochondrial signaling events.
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