Kidney cell death in inflammation: The role of oxidative stress and mitochondria

Pyelonephritis is an infectious disease, and common treatment strategy is based on antibiotic therapy directed at the elimination of a pathogen. However, urinary tract infections are accompanied by inflammation and oxidative stress, which are major damaging factors, and therefore can serve as a target for therapeutic intervention. The goal of this study was to clarify the role of the mitochondrial reactive oxygen species (ROS) in kidney cell damage under experimental pyelonephritis. We investigated the mechanisms of inflammation and the role of mitochondria and oxidative stress in inflammation in kidney tissue using in vivo and in vitro models of pyelonephritis. We observed the development of oxidative stress in renal tubular epithelium in vitro, and resulting apoptotic cell death. This oxidative damage was caused by the leukocytes producing ROS after interaction with bacterial antigens. The essential role of mitochondria-mediated oxidative stress was confirmed using an experimental model of pyelonephritis in vivo. We revealed increased levels of malonic dialdehyde in kidneys of rats with experimental pyelonephritis that pointed to lipid peroxidation. Besides, high ROS levels were observed in blood leukocytes from rats with pyelonephritis. The mitochondria-targeted antioxidant SkQ1 significantly reduced the signs of kidney inflammatory injury, in particular the infiltration of neutrophils. Summarizing the data obtained, we assume the importance of mitochondrial ROS in different phases of acute pyelonephritis onset. Protection of kidney cells from infection-mediated damage can be attained by the induction of tolerance mechanisms and by antioxidant treatment.     

Singlet oxygen scavenging activity of tocopherol and plastochromanol in Arabidopsis thaliana: relevance to photooxidative stress

In the present study, singlet oxygen (¹O₂) scavenging activity of tocopherol and plastochromanol was examined in tocopherol cyclase‐deficient mutant (vte1) of Arabidopsis thaliana lacking both tocopherol and plastochromanol. It is demonstrated here that suppression of tocopherol and plastochromanol synthesis in chloroplasts isolated from vte1 Arabidopsis plants enhanced ¹O₂ formation under high light illumination as monitored by electron paramagnetic resonance spin‐trapping spectroscopy. The exposure of vte1 Arabidopsis plants to high light resulted in the formation of secondary lipid peroxidation product malondialdehyde as determined by high‐pressure liquid chromatography. Furthermore, it is shown here that the imaging of ultra‐weak photon emission known to reflect oxidation of lipids was unambiguously higher in vte1 Arabidopsis plants. Our results indicate that tocopherol and plastochromanol act as efficient ¹O₂ scavengers and protect effectively lipids against photooxidative damage in Arabidopsis plants.     

Lithium salts — Simple but magic

For many decades pharmacological drugs based on lithium salts have been successfully used in psychiatry to treat bipolar disorder, and they remain the “gold standard” of pharmacological therapy of patients with this disease. At the same time, over recent years in experiments in vitro and in vivo a plethora of evidence has accumulated on a positive effect of lithium ions in other areas including their neuro-, cardio-, and nephroprotective properties, regulation of stem cells functions, regulation of inflammation, and others. Numerous studies have shown that the effect of lithium ions involves several mechanisms; however, one of its main targets in the implementation of most of the effects is glycogen synthase kinase 3β, a key enzyme in various pathological and protective signaling pathways in cells. However, one of the main limitations of the use of lithium salts in clinics is their narrow therapeutic window, and the risk of toxic side effects. This review presents the diversity of effects of lithium ions on the organism emphasizing their potential clinical applications with minimal undesirable side effects. In the end, we present a schematic “Lithiometer”, comparing the range of Li⁺ concentrations that might be used for the treatment of acute pathologies with possible toxic effects of Li⁺.     

Bacterial therapy and mitochondrial therapy

Current methods for treatment of cellular and organ pathologies are extremely diverse and constantly evolving, going beyond the use of drugs, based on chemical interaction with biological targets to normalize the functions of the system. Because pharmacological approaches are often untenable, recent strategies in the therapy of different pathological conditions are of particular interest through introducing into the organism of some living system or its components, in particular, bacteria or isolated subcellular structures such as mitochondria. This review describes the most interesting and original examples of therapy using bacteria and mitochondria, which in perspective can dramatically change our views on the principles for the treatment of many diseases. Thus, we analyze such therapeutic effects from the perspective of the similarities between mitochondria and bacteria as the evolutionary ancestors of mitochondria.     

Mitochondria as a target for neuroprotection

Despite all the efforts of modern medical and biomedical sciences, the effective therapeutic treatments that would restore the brain functions lost after stroke have not been found yet. At the same time, experimental preclinical studies revealed an arsenal of effectors having potential for clinical applications. Identification of the key signaling pathways, both damaging and protective, can accelerate the development and implementation of new effective neuroprotectors. One of the key elements of these pathways is mitochondrion. In this context, we studied various therapeutic approaches to the treatment and prevention of cerebral ischemia, which are aimed at modulation of mitochondrial functions. The spectrum of tested neuroprotectors included antioxidants, uncouplers of respiration and phosphorylation, as well as ischemic, remote, and pharmacological preconditioning. Their efficacy and therapeutic windows were compared and the possibility of combining different methods in order to maximize their efficiency was considered.     

Quantification of mitochondrial morphology in situ

The structural organization of mitochondria reflects their functional status and largely is an index of cell viability. The indirect parameter to assess the functional state of mitochondria in cells is the degree of their fragmentation, i.e., the ratio of long or branched mitochondrial structures to round mitochondria. Such evaluations requires an approach that allows to create an integral pattern of the three-dimensional organization of mitochondrial reticulum using confocal images of mitochondria stained with a fluorescent probe. In the present study, we tested three approaches to analyzing the structural architecture of mitochondria under normal conditions and fission induced by oxidative stress. We revealed that, while the most informative is a three-dimensional reconstruction based on series of confocal images taken along the Z-dimension, with some restrictions it is plausible to use more simple algorithms of analysis, including one that uses unitary twodimensional images. Further improvement of these methods of image analysis will allow more comprehensive study of mitochondrial architecture under normal conditions and different pathological states. It may also provide quantification of a number of mitochondrial parameters determining the morphofunctional state of mitochondria—primarily, their absolute and relative volumes—and give additional information on threedimensional organization of the mitochondrion.