Mitochondrial electron transport chain, ROS generation and uncoupling (Review)

Abstract

The mammalian mitochondrial electron transport chain (ETC) includes complexes I-IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I-IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O 2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites I F and I Q in complex I, site II F in complex II and site III Qo in complex III, and the physiological and pathological regulation of ROS. As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a number of diseases are closely related to ROS overproduction. Finally, proton leak and uncoupling proteins (UCP S ) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1-5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temperature in a cold environment through non-shivering thermogenesis. The core role of UCP2-5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are associated with UCPs.

Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

“…It is unclear how YAP1 stimulated mtROS and further studies are required to establish the mechanism(s) of the YAP1-mediated regulation of mtROS. mtROS is generated via the electron transport system [69] and NOX4, which is localized in the mitochondria [70][71][72][73][74][75][76]. NOX4 expression is increased in IPF lung specimens and IPF fibroblasts, and increased NOX4 expression is associated with pro-fibrotic phenotype [77,78].…”

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

“…ROS production occurs in particular at high NADH/NAD + ratios and at a high mitochondrial membrane potential ΔΨ m [23,24]. In addition to various other sites in mitochondria, ROS are mainly produced from complexes I and III [24][25][26][27][28]. Overproduction of ROS could lead to oxidative damage of lipids, DNA, and proteins [29,30].…”

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

“…These changes in function were, however, not reflected in impaired mitochondrial integrity as judged by citrate synthase (CS) activity ( Figure 5E), or morphology as analyzed by transmission electron microscopy ( Figure 5F). Inhibition of ETC function can lead to the generation of reactive oxygen species (ROS) (Zhao et al, 2019). To investigate the effect of doxycycline treatment in the generation of ROS we treated HepG2 cells with doxycycline for 24 h and used the MitoSOX fluorescent reporter to measure peroxide ROS generation by cytometry.…”