Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

ABSTRACT When trying to reconstruct the evolutionary trajectories during early eukaryogenesis, one is struck by clear differences in the developments of two organelles of endosymbiotic origin: the mitochondrion and the chloroplast. From a symbiogenic perspective, eukaryotic development can be interpreted as a process in which many of the defining eukaryotic characteristics arose as a result of mutual adaptions of both prokaryotes (an archaeon and a bacterium) involved. This implies that many steps during the bacterium-to-mitochondrion transition trajectory occurred in an intense period of dramatic and rapid changes. In contrast, the subsequent cyanobacterium-to-chloroplast development in a specific eukaryotic subgroup, leading to the photosynthetic lineages, occurred in a full-fledged eukaryote. The commonalities and differences in the two trajectories shed an interesting light on early, and ongoing, eukaryotic evolutionary driving forces, especially endogenous reactive oxygen species (ROS) formation. Differences between organellar ribosomes, changes to the electron transport chain (ETC) components, and mitochondrial codon reassignments in nonplant mitochondria can be understood when mitochondrial ROS formation, e.g., during high energy consumption in heterotrophs, is taken into account. IMPORTANCE The early eukaryotic evolution was deeply influenced by the acquisition of two endosymbiotic organelles - the mitochondrion and the chloroplast. Here we discuss the possibly important role of reactive oxygen species in these processes.

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Role of reactive oxygen species in the pathogenesis of diabetic nephropathy

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2008.09.017 ◽

2008 ◽

Vol 82 ◽

pp. S42-S45 ◽

Cited By ~ 142

Author(s):

Hunjoo Ha ◽

In-A Hwang ◽

Jong Hee Park ◽

Hi Bahl Lee

Keyword(s):

Reactive Oxygen Species ◽

Diabetic Nephropathy ◽

Reactive Oxygen ◽

Oxygen Species

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Mitochondrial reactive oxygen species-mediated signaling in endothelial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01283.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2023-H2031 ◽

Cited By ~ 270

Author(s):

David X. Zhang ◽

David D. Gutterman

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Cells ◽

Cell Signaling ◽

Vascular Endothelial Cells ◽

Reactive Oxygen ◽

Vascular Endothelial ◽

Ros Production ◽

Oxygen Species ◽

Mitochondrial Ros

Once thought of as toxic by-products of cellular metabolism, reactive oxygen species (ROS) have been implicated in a large variety of cell-signaling processes. Several enzymatic systems contribute to ROS production in vascular endothelial cells, including NA(D)PH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase, and the mitochondrial electron transport chain. The respiratory chain is the major source of ROS in most mammalian cells, but the role of mitochondria-derived ROS in vascular cell signaling has received little attention. A new paradigm has evolved in recent years postulating that, in addition to producing ATP, mitochondria also play a key role in cell signaling and regulate a variety of cellular functions. This review focuses on the emerging role of mitochondrial ROS as signaling molecules in vascular endothelial cells. Specifically, we discuss some recent findings that indicate that mitochondrial ROS regulate vascular endothelial function, focusing on major sites of ROS production in endothelial mitochondria, factors modulating mitochondrial ROS production, the physiological and clinical implications of endothelial mitochondrial ROS, and methodological considerations in the study of mitochondrial contribution to vascular ROS generation.

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Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus

Frontiers in Immunology ◽

10.3389/fimmu.2021.641495 ◽

2021 ◽

Vol 12 ◽

Author(s):

Remi Hatinguais ◽

Arnab Pradhan ◽

Gordon D. Brown ◽

Alistair J. P. Brown ◽

Adilia Warris ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Aspergillus Fumigatus ◽

Reactive Oxygen ◽

Oxygen Species ◽

Mitochondrial Ros ◽

Tnf Α ◽

Reverse Electron Transport ◽

Phagosomal Membrane ◽

Antimicrobial Immunity

Reactive Oxygen Species (ROS) are highly reactive molecules that can induce oxidative stress. For instance, the oxidative burst of immune cells is well known for its ability to inhibit the growth of invading pathogens. However, ROS also mediate redox signalling, which is important for the regulation of antimicrobial immunity. Here, we report a crucial role of mitochondrial ROS (mitoROS) in antifungal responses of macrophages. We show that mitoROS production rises in murine macrophages exposed to swollen conidia of the fungal pathogen Aspergillus fumigatus compared to untreated macrophages, or those treated with resting conidia. Furthermore, the exposure of macrophages to swollen conidia increases the activity of complex II of the respiratory chain and raises mitochondrial membrane potential. These alterations in mitochondria of infected macrophages suggest that mitoROS are produced via reverse electron transport (RET). Significantly, preventing mitoROS generation via RET by treatment with rotenone, or a suppressor of site IQ electron leak, S1QEL1.1, lowers the production of pro-inflammatory cytokines TNF-α and IL-1β in macrophages exposed to swollen conidia of A. fumigatus. Rotenone and S1QEL1.1 also reduces the fungicidal activity of macrophages against swollen conidia. Moreover, we have established that elevated recruitment of NADPH oxidase 2 (NOX2, also called gp91phox) to the phagosomal membrane occurs prior to the increase in mitoROS generation. Using macrophages from gp91phox-/- mice, we have further demonstrated that NOX2 is required to regulate cytokine secretion by RET-associated mitoROS in response to infection with swollen conidia. Taken together, these observations demonstrate the importance of RET-mediated mitoROS production in macrophages infected with A. fumigatus.

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Reactive Oxygen Species in Macrophages: Sources and Targets

Frontiers in Immunology ◽

10.3389/fimmu.2021.734229 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marcella Canton ◽

Ricardo Sánchez-Rodríguez ◽

Iolanda Spera ◽

Francisca C. Venegas ◽

Maria Favia ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Signaling Networks ◽

Oxygen Species ◽

Cellular Processes ◽

Pathological Conditions ◽

Mitochondrial Ros ◽

Ros Formation ◽

Excessive Accumulation

Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the “all or none” pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources.

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