Mitochondrial proton and electron leaks

Abstract

Mitochondrial proton and electron leak have a major impact on mitochondrial coupling efficiency and production of reactive oxygen species. In the first part of this chapter, we address the molecular nature of the basal and inducible proton leak pathways, and their physiological importance. The basal leak is unregulated, and a major proportion can be attributed to mitochondrial anion carriers, while the proton leak through the lipid bilayer appears to be minor. The basal proton leak is cell-type specific and correlates with metabolic rate. The inducible leak through the adenine nucleotide translocase (ANT) and uncoupling proteins (UCPs) can be activated by fatty acids, superoxide, or peroxidation products. 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 second part of the chapter focuses on the electron leak that occurs in the mitochondrial electron transport chain. Exit of electrons prior to the reduction of oxygen to water at cytochrome c oxidase causes the production of superoxide. As the mechanisms of electron leak are crucial to understanding their physiological relevance, we summarize the mechanisms and topology of electron leak from Complex I and III in studies using isolated mitochondria. We also highlight recent progress and challenges of assessing electron leak in the living cell. Finally, we emphasise the importance of proton and electron leak as therapeutic targets in body weight regulation and insulin secretion.

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…This supports the hypothesis that ANT participates to a first line of defense against ROS in response to fatty acids, superoxide and lipid peroxidation products under conditions of high oxidative damage (Figure 1) (Scho¨nfeld et al, 1996;Khailova et al, 2006;Azzu et al, 2008;Jastroch et al, 2010;Toime and Brand, 2010). This ANT , 2003).…”

Redox regulation of mitochondrial functional activity by quinones

“…However, because they are not a primary substrate of these enzymes, the efficiency of oxidation/reduction has to be strongly dependent on the availability of primary substrates and "saturation" of electrons in the ETC (reduction states of components of ETC), just as the electron leak from ETC and superoxide production depend on the reduction states of ETC components and the proton gradient (25). In the absence of ADP, the mitochondrial membrane potential, stored as a proton gradient, is not consumed on ATP production and ETC is saturated, providing favorable conditions for reduction of exogenous quinones by ETC complexes, and, therefore, the greatest changes in oxygen consumption due to the reduction of quinones should be revealed for V 2 respiration rate.…”

The Serum Irisin Level in Non-Diabetic Patients with Chronic Kidney Disease

“…Another mechanism may be an increase in energy expenditure as a result of activation of tissue mitochondrial uncoupling proteins (UCPs) due to proinflammatory cytokines (8). UCPs are integral membrane proteins in the mitochondria of skeletal muscle and brown adipose tissue (9) UCPs cause protons to enter the mitochondrial matrix from the intermembrane space, without participating in the synthesis of adenosine triphosphate (ATP) (10). As a result of such transport of protons, ATP is not synthesized.…”