Abstract
Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.
Highlights
Chronic kidney disease (CKD) is a potentially life-threatening complication of kidney pathologies that affects more than 10% of the human population worldwide
The analysis revealed that among all uremic toxins, more than 20% are either completely synthesized in mitochondria under normal conditions, or at least are closely associated with mitochondrial metabolic pathways (Figure 1)
The synthesis of which are related to the mitochondria (Table 1), phenylacetylglutamine is worth mentioning, due to it being a toxin with blood concentrations in excess of more than 100 times the normal during CKD, the levels of which are used as a mortality index [32]
Summary
Chronic kidney disease (CKD) is a potentially life-threatening complication of kidney pathologies that affects more than 10% of the human population (more than 850 million people) worldwide. While uremia has clearly recognized clinical symptoms, elucidation of the molecular and cellular mechanisms of disease progression is a very challenging task This is because more than one hundred molecules are considered to be “uremic toxins” [4], making it extremely difficult to analyze their diverse effects on different tissues and cell types and the possibility of interplay of such effects. CKD, uremia, and the pleiotropic effects of uremic toxins are so vast and diverse in affecting most of the organs and signaling pathways that even up to the present day there is no widely accepted “synthetic understanding” of the patho-physiology of CKD This is due to the comprehensive mechanisms of this pathology being rather “mosaic” and in a fragmented state. In this review, we discuss the novel role of the mitochondrion in the context of both the target and source of pathological pathways and compounds prevalent in uremia, which may present a novel paradigm and offer new avenues of investigation
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