Development of mitochondrial dysfunction and oxidative stress in chronic kidney disease

Abstract

Finding new pathogenic factors that affect the progression of chronic diseases is an important step in the fight against these diseases. In this review, the causes and role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) are considered. In this context, the importance of mitochondria for kidney cells in general and proximal tubule cells in particular, as well as the role of oxidative stress in the pathogenesis of CKD, are also discussed. The causes of mitochondrial dysfunction in CKD and the consequences of the development of pathological conditions as a result of impaired mitochondrial activity are analyzed in detail.

Introduction

Chronic kidney disease (CKD) is defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min, persisting for 3 months or more, regardless of cause. ¹ This is a condition of progressive loss of kidney function that eventually leads to the need for kidney replacement therapy (dialysis or transplant). Kidney injury refers to pathologic abnormalities suggested by imaging studies or kidney biopsy, urinary sediment abnormalities, or an increased rate of urinary albumin excretion. ²

The true incidence and prevalence of CKD is difficult to determine due to the asymptomatic nature of early and moderate CKD. The prevalence of CKD ranges from 10% to 14% in the general population. ³ The causes of CKD vary worldwide and the most common primary diseases causing CKD and ultimately kidney failure are: type 1 and type 2 diabetes mellitus, hypertension, primary glomerulonephritis, chronic tubulointerstitial nephritis, hereditary or cystic diseases, secondary glomerulonephritis or vasculitis, plasma dyscrasias or neoplasms, sickle cell nephropathy. CKD can result from pathological processes in any of three categories: prekidney (decreased kidney perfusion pressure), intrinsic kidney (pathology of vessels, glomeruli, or tubules-interstitium), or postkidney (obstructive). ⁴

Community-acquired CKD occurs mainly in the elderly. These people have been exposed throughout their lives to risk factors for cardiovascular disease, hypertension and diabetes, which can also affect the kidneys. The average rate of GFR decline in this population ranges from 0.75 to 1 mL/min at the age of 40 to 50 years. ⁵ Unlike community-acquired CKD, patients with said CKD present early in life due to hereditary (autosomal dominant polycystic kidney disease, ADPKD) or acquired nephropathy (glomerulonephritis, diabetic nephropathy (DN), or tubulointerstitial disease) causing progressive kidney damage and loss of function. The rate of progression of the mentioned CKD varies depending on the underlying disease and in different patients. It has been shown that DNhas a rapid rate of decrease in GFR, averaging about 10 mL/min/year. ²

Patients with CKD have a reduced ability to maintain fluid balance after a rapid sodium load, which becomes more pronounced in the later stages of the disease. Metabolic acidosis is a common complication of progressive CKD due to the increased tendency of the kidneys in CKD to retain H2. Chronic metabolic acidosis in CKD can lead to osteopenia, increased protein catabolism, and secondary hyperparathyroidism. CKD is a significant risk factor for cardiovascular disease, and the risk increases with increasing severity of CKD. Hyperphosphatemia is also a common complication of CKD due to reduced filtered phosphorus load. This leads to increased secretion of parathyroid hormone (PTH) and causes secondary hyperparathyroidism. ⁶

Treatment of CKD is based on treatment of reversible causes of kidney failure, slowing the progression of CKD, and kidney replacement therapy. When CKD progresses to kidney failure, kidney replacement therapy becomes essential for patient survival. However, the current situation with treatment leaves much to be desired. Currently, more than two million patients worldwide are undergoing dialysis or transplantation, but this number may be only 10% of those who actually need treatment to survive. Every year, CKD kills about a million people. ⁷

Although oxidative stress and mitochondrial dysfunction are discussed in many research and review articles, this review has a key distinctive feature associated with the construction of a pathological model of the development of CKD, in which mitochondrial dysfunction and oxidative stress play a central role. This model allows to better understand the role of these processes in the pathogenesis of CKD.

Pathogenesis of chronic kidney disease

Extracellular matrix (ECM) deposition and kidney cell death are the pathophysiological signs of chronic kidney disease (CKD). Progressive kidney disease is defined by morphological changes, such as kidney inflammation, glomerulosclerosis, tubular atrophy, tubulointerstitial fibrosis, and capillary rarefaction, regardless of the original lesion. A gradual process known as the pathophysiology of kidney fibrosis, which includes glomerulosclerosis and interstitial fibrosis, ultimately results in end-stage kidney disease, a debilitating illness that necessitates kidney replacement treatment. ⁸ kidneykidneykidneykidney

Glomerulosclerosis

Increased mesangial matrix buildup and glomerular capillary obliteration are hallmarks of glomerulosclerosis. Even more intricate, the underlying pathogenic process of glomerulosclerosis can be split into many distinct stages. Prior to the release of numerous cytokines and chemokines that draw monocytes, lymphocytes, neutrophils, and other types of cells associated with inflammation to the site of injury, glomerular resident cells are damaged and activated due to a variety of risk factors, including arterial hypertension, dyslipidemia, and/or the accumulation of immune complexes. ⁹

Second, along with to their own cells, these infiltrating cells also produce other growth factors and cytokines, such as interferon gamma (IFN-γ), transforming growth factor β1 (TGF-β1), platelet growth factor (PDGF), fibroblast growth factor (FGF), tumor necrosis factor (TNF), and angiotensin. These factors and cytokines lead to capillary collapse and obliteration, podocyte loss, and activation of parietal epithelial cells. ¹⁰ Fibrogenesis, the last stage, is the creation of new ECM components to replace injured tissue. This process creates a scaffold that allows for wound closure, transformation, and healing. Thus, mesangial cell proliferation and matrix synthesis, endothelial dysfunction and injury, and podocyte damage are the major causes of glomerulosclerosis. ¹¹ A prominent sign of proteinuric glomerulopathies, such as DN, amyloid nephropathy, membranous proliferative glomerulonephritis (MPGN), focal segmental glomerulosclerosis, and minimal change disease, is podocyte destruction. Damage to podocytes is primarily caused by four mechanisms: modifications to the glomerular basement membrane, molecular alterations in the slit diaphragm or structural rupture, actin cytoskeleton malfunction in podocytes, and modifications to the negative surface charge on podocytes. Podocytes undergo a range of adaptive alterations following a stroke, including hypertrophy, transdifferentiation, dedifferentiation, detachment, and death. The degree and length of the stroke mostly determine these podocyte adaptive responses. ¹²

The juxtaglomerular apparatus and extraglomerular mesangium are continued by the mesangial cells that comprise the glomerulus’s central stalk. MPGN, DN, lupus nephritis (LN), IgA nephropathy (IgAN), and other glomerular disorders are characterized by mesangial cell proliferation. Glomerulosclerosis is thought to be facilitated by mesangial cell proliferation and matrix buildup, which are induced by several profibrotic agents such as TGF-β, PDGF, and fibroblast growth factor 2 (FGF2). The key damage factors cause mesangial cells to differentiate into mesangioblasts. The latter have the capacity to overproduce extracellular matrix, which results in the growth of mesangia, a precursor to glomerulosclerosis. 1 ¹³

Kidney interstitial fibrosis

Excessive ECM deposition in the interstitial compartment is a characteristic of kidney interstitial fibrosis, a disease of wound healing that follows initial injury. Nearly every type of cell, including non-resident and resident kidney cells, is involved in the pathophysiology of kidney interstitial fibrosis. Inflammatory cellular infiltration, fibroblast activation and myofibroblast growth from different cell types, production and deposition of extracellular matrix molecules, and tubular atrophy with microvascular rarefaction are important cellular and molecular processes. ¹⁴ It is possible to devide kidney interstitial fibrosis into four separate stages. kidney1) Kidney cells sustain damage during chronic injury (such as proteinuria, hyperglycemia, or hypoxemia), and they produce chemotactic proteins that serve as a signal to draw inflammatory cells to the region of injury. ¹⁵ 2) Kidney cell damage is exacerbated by infiltrating inflammatory cells that produce different chemicals, such as reactive oxygene species (ROS), and several protein factors, such as monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-alpha (TNFα), interleukin-1 (IL-1), transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and angiotensin II (Ang II). Fibroblasts and other cell types, such as tubular epithelial cells, pericytes, and endothelial cells, are stimulated by this sequence of events and may go through phenotypic activation or change to produce more ECM components. ¹⁶ 3) Activated myofibroblasts can come from several sources and produce ECM. ECM accumulation in the kidney interstitium causes the kidney tubules to atrophy and undergo apoptosis. ¹⁷ Kidneykidney 4) The formation of excess matrix in the kidneys is caused by abnormalities in the breakdown of extracellular matrix and excessive matrix synthesis. Due to the extracellular matrix’s tendency to proteolyze, kidney interstitial fibrosis may be reversible in its early stages. But in the latter stages of kidney fibrosis, cross-linking with tissue transglutaminase and lysyl oxidase is assumed to alter the matrix as damage continues and fibrosis advances, ultimately leading the matrix to become stiff and extremely resistant to proteolysis. ⁸ Microvascular rarefaction, kidney function loss, and ultimately kidney parenchyma damage are the results of excessive extracellular matrix deposition. kidneykidneykidneykidney

Ways of development of oxidative stress

The overabundance of ROS in cells and tissues that cannot be neutralized by the antioxidant system is referred to as oxidative stress. DNA, proteins, and lipids are examples of the molecules that can be harmed by an imbalance in this protection system. ¹⁸ ROS are usually produced in the body in a limited amount and are important compounds involved in the regulatory function associated with the maintenance of cellular homeostasis and functions such as signaling, gene expression, and receptor activation. ¹⁹ Mitochondrial oxidative metabolism in cells produces ROS forms and organic peroxides during cellular respiration. ²⁰ Furthermore, nitric oxide can also be produced during the respiratory chain reaction in hypoxic environments. ²¹ The aforementioned reactive nitrogen species (RNS) have the ability to generate other reactive forms, including malondialdehyde, 4-hydroxynonenal, and reactive aldehydes. Proteins, fats, and DNA/RNA are the primary targets of oxidative stress, and changes to these molecules can raise the risk of mutagenesis. Overproduction of ROS and RNS, particularly when it occurs over an extended length of time, can lead to somatic mutations, preneoplastic and neoplastic changes, and harm to the structure and function of cells. ²²

Inflammation is a pathological condition characterized by the infiltration of immune cells (monocytes, macrophages, lymphocytes, neutrophils, and plasma cells) into the vessel wall, extravasation of immune cells into tissues, and release of ROS by these cells, resulting in tissue damage. Neutrophils generate ROS predominantly via the enzyme NADPH oxidase-2, whose activity is mediated by the assembly of the gp91phox (NOX2) catalytic subunit. O2 is formed spontaneously or enzymatically dismutates into H2O2. When the enzyme MPO is involved, H2O2 can also produce additional extremely reactive radicals such the hydroxyl radical (·OH) or hypochlorous acid (HOCl). These two radicals not only oxidize different proteins but also have the ability to harm tissue. ²³ In addition to directly producing oxidative stress to eliminate pathogens, ROS produced by inflammatory cells also activate pathways that result in greater inflammation. Pro-inflammatory cytokines and chemokines are produced as a result of ROS-induced activation of kinases, or enzymes that promote phosphorylation, such as c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). This also activates transcription factors. These cytokines and chemokines are known to produce ROS when they bind to their corresponding receptors, which include the platelet-derived growth factor receptor, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR). ²²

ROS causes the expression of plasminogen activator inhibitor-1 (PAI-1), macrophage migration inhibitory factor (MMIF), matrix metalloproteinases (MMP-9) and (MMP-2), and monocyte chemoattractant proteins-1 and 2 (MCP-1/2), macrophage inflammatory protein (MIP-1/2), and RANTES, in addition to facilitating the production of cytokines such as TNF-α, interleukins (IL-1 and -6). The intricate mechanisms of recruitment and attachment involve the regulation of immune cell contact with vessel walls by cell adhesion molecules and the management of inflow through a cytokine-chemokine gradient. The substances PAI, MMIF, and MMP come next, which aid in immune cell migration into tissues. Immune cells release various proteases and oxidants once they are activated. The serine protease neutrophil elastase, which has a direct antibacterial action, is produced by neutrophils. Not only ROS but also other free radicals, such HOCl, result from the catalysis of H2O2 by MPO, an enzyme that is widely present in immunological and inflammatory cells. Proteases are among the chemicals that highly reactive HOCl may oxidize, that lead to tissue damage. Oxidative stress and the production of ROS can perpetuate the process of inflammation, which can lead to a chronic illness that aggravates a number of inflammatory diseases. ²³ Recent developments in our comprehension of the intricate nature of inflammatory signaling indicate the existence of several pathways that become active upon identification of molecular patterns originating from either oxidative damage or infections. Therefore, immunological receptors have the ability to detect endogenous stress- or pathogen-associated molecular patterns (PAMPs) as a consequence of invasion, as well as hazard-associated molecular patterns (DAMPs) as a result of endogenous stress, and then initiate subsequent signaling cascades. Inflammasomes are multiprotein complexes that form in response to PAMP or DAMP; they trigger the caspase signaling cascade, which results in cellular deterioration and death. ²⁴ Inflammasome-induced cell destruction and apoptosis worsen and contribute to the pathophysiology of inflammatory disorders. In fact, inflammasomes have been linked to a wide range of inflammatory illnesses, including metabolic (obesity, atherosclerosis, and type 2 diabetes) and neurodegenerative disorders (multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease). ²⁵ ROS-induced signals release adhesion molecules, cytokines, chemokines, and growth factors that in turn drive inflammation; on the other hand, inflammatory processes that generate ROS and other oxidants also lead to oxidative stress and damage. ²⁶ The pathways through which oxidative stress develops are summarized in Figure 1.

Figure 1.

Ways of development of oxidative stress.

Development of mitochondrial dysfunction in the pathogenesis of chronic kidney disease

The role of mitochondria for the functioning of kidney cells

Since the kidneys are one of the most energy-consuming organs in the human body, consuming about 7% of the daily energy of ATP, ²⁷ which accordingly makes them also leaders in the number of mitochondria in the cell (second place after the heart). ²⁸ As is well known, mitochondria provide cells with energy in the form of ATP molecules, which are generated by the process of oxidative phosphorylation. It is noted that different parts of the nephron differ in different density and number of mitochondria due to different energy needs. Kidney proximal tubular cells are the most dependent on energy needs due to the need to maintain the ATP pool to ensure high-energy processes of reabsorption and secretion of various compounds (glucose, albumin, ions) that go against concentration gradients. ²⁹ It is known that the kidney proximal tubular cells are able to absorb more than 65% of the filtrate that passes through the globular membrane filter. ³⁰ In this regard, proximal tubular cells require more efficient production of ATP, which is provided by predominant oxidative phosphorylation in mitochondria, in contrast to some other cell populations of the kidneys, such as mesangial cells, endothelial cells and podocytes, which use the glycolytic pathway to a greater extent for obtaining energy. ³¹ It should also be noted that the predominant energy substrate in proximal tubule cells is fatty acids rather than glucose, which also determines the process of fatty acid β-oxidation occurring in the mitochondrial matrix as one of the key stages of energy metabolism in proximal tubule cells. ³⁰ Based on the foregoing, the correct functioning of mitochondria is necessary for the functioning of the kidneys, especially for the cells of the proximal tubules, where the main kidney function, filtration, is carried out. In this regard, the occurrence of mitochondrial dysfunction in kidney cells is potentially an extremely dangerous situation for the overall functioning of the kidneys, as well as for the development of various pathological mechanisms in CKD.

Factors in the development of mitochondrial dysfunction

The occurrence of mitochondrial dysfunction in CKD has been demonstrated in several studies.^32,33 At the same time, the role of mitochondrial dysfunction and its place in the overall pathogenesis of CKD is still not completely clear. We consider the main reasons that, in our opinion, influence the occurrence of mitochondrial dysfunction in CKD. It is known that DN caused by various types of diabetes is one of the main causes of CKD. ³⁴ The resulting hyperinsulinemia is the cause of the accumulation of lipids in various tissues and organs in addition to adipose tissue, including the kidneys. This accumulation of lipids leads to cell damage, a process known as lipotoxicity. ³⁵ It is noted that in DN, there is a decrease in β-oxidation of fatty acids and an increase in the accumulation of lipids in the cell in the form of drops. ³⁶ These events lead to the following disastrous consequences. First, since β-oxidation of fatty acids is often the main way to obtain energy in the kidneys, its inhibition leads to a state of energy deficiency, which is a critical event for the cells of the proximal tubules of the kidneys due to the need to maintain a constant work of energy-consuming reabsorption processes. Secondly, the accumulation of lipids within the cells themselves can also have a lipotoxic effect, damaging macromolecules, including proteins, RNA, and DNA of mitochondria, which directly leads to mitochondrial dysfunction. ³⁰ Thirdly, fatty acids that accumulate in the mitochondrial matrix and do not undergo degradation are directly convenient targets for peroxidation caused by ROS and thus indirectly cause damage to the mitochondria themselves and their dysfunction. ³⁷ Another noted consequence of diabetic cardiomyopathy is the modulation of mitochondrial dynamics processes. Thus, an important marked event directly related to the development of mitochondrial dysfunction in CKD is the suppression of mitochondrial biogenesis, which was demonstrated as a result of the analysis of the inhibition of the Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) factor responsible for mitochondrial synthesis. PGC-1α is an meaningful transcriptional regulator that works in concert with numerous transcription factors that have a wide range of tissue distributions and functions to control target genes. These transcription factors include the liver X receptor-alpha (LXRα), glucocorticoid receptor (GR), hepatic nuclear factor 4 (HNF-4), and nuclear receptor PPAR-γ. It is generally known that PGC-1α regulates oxidative stress (OS), energy metabolism, and mitochondrial biosynthesis. ³⁸ Thus, in various models ofDN, it was shown that the levels of PGC-1α were reduced.^39,40 In another study in a mouse model of CKD, it was shown that the use of transgenic PGC-1α in kidney tubular cells led to an improvement in kidney histology, which was associated with an increase in ATP production and an increase in fatty acid oxidation. ⁴¹ In addition, in CKD, there is an increased fission of mitochondria, which also contributes to the development of mitochondrial dysfunction. ⁴² Mitochondrial fission is necessary to increase the number of mitochondria and the subsequent segregation of healthy mitochondria from diseased ones. However, at high levels of mitochondrial fission, the number of dysfunctional mitochondria increases, and the resulting new healthy mitochondria are smaller in size than the parent ones and, accordingly, have a shorter service life (the further appearance of mitochondria of ever smaller size leads to an increase in the proportion of dysfunctional mitochondria). A number of studies have shown that inhibition of the activity of the main activator of mitochondrial division, the dynamin-related protein 1 (Drp1), led to an improvement in mitochondrial function in kidney cells. 4^43,44 Since acute kidney injury (AKI) may be the cause of CKD, the underlying causes of its progression may also be associated with the initiation of CKD. ²⁹ It is known that one of the most common causes of AKI is ischemia-reperfusion injury (IRI) of the kidneys, which occurs as a result of a strong decrease in the supply of oxygen and nutrients to the kidneys. ⁴⁵ This event directly affects the inhibition of oxidative phosphorylation, the development of oxidative stress with subsequent damage to mitochondria, and necrotic cell death. Another cause of AKI may be exposure to nephrotoxic compounds such as certain chemotherapy drugs such as cisplatin. It has been shown that cisplatin can affect kidney mitochondria, causing structural disturbances in the cristae of the inner mitochondrial membrane, depletion of mitochondrial DNA, a decrease in the mass of mitochondria, and inhibition of the activity of the electron transport chain (ETC) enzyme, cytochrome C oxidase, which leads to mitochondrial dysfunction. ⁴⁶ The general scheme for the development of mitochondrial dysfunction in CKD is shown in Figure 2.

Figure 2.

Model of development of mitochondrial dysfunction in Chronic kidney disease.

Consequences of mitochondrial dysfunction in chronic kidney disease

Two events mediated by the onset of mitochondrial dysfunction in CKD are a decrease in ATP production and the development of oxidative stress. A decrease in ATP production, directly caused by a disruption of the process of oxidative phosphorylation, leads to energy dysfunction of kidney cells, primarily cells of the proximal tubules, and the initiation of apoptosis. Oxidative stress has properties that make it a useful factor in disease progression. First, ROS produced in large quantities by dysfunctional mitochondria damage mitochondrial proteins and DNA, further enhancing ROS production. Thus, oxidative stress is a self-sustaining process. Secondly, oxidative stress causes an increase in the permeability of the mitochondrial membrane, which leads to the release of cytochrome C into the cytoplasm and direct activation of the internal pathway of apoptosis. Third, as noted in the previous section, oxidative stress initiates an inflammatory response in a complex manner. In addition, in a study. 4 ⁴⁷ it was found that the development of oxidative stress caused by mitochondrial dysfunction in patients with CKD led to cutaneous vasodilation and the development of microvascular dysfunction, which was a high risk of further development of cardiovascular diseases. In CKD, chronic inflammation can develop, especially in dialysis patients, leading to worsening of their condition. One of the factors in the development of chronic inflammation in CKD is oxidative stress. ⁴⁸ The spread of oxidative stress in CKD may be associated with a weakening of antioxidant protection. Thus, proteomic analysis on hypoxic rat kidneys revealed a sharp decrease in the expression of one of the main antioxidant enzymes, superoxide dismutase (SOD). ⁴⁹ In another study in a mouse model of cisplatin-induced AKI, a decrease in antioxidant protection was also observed, which, however, was restored by the introduction of an artificial antioxidant supplement - CoQ10, which identifies antioxidant drugs as potential therapeutic agents for the treatment of kidney disease. ⁵⁰ The role of oxidative stress in CKD is shown in Figure 3.

Figure 3.

Scheme of the influence of oxidative stress in the pathogenesis of chronic kidney disease.

Discussion

In view of the fact that mitochondrial dysfunction is inextricably linked with the development of oxidative stress, it is advisable to consider the use of compounds with antioxidant properties as a possible way to treat CKD and, first of all, the use of already registered drugs with antioxidant properties by repurposing them for the treatment of CKD or at least phase II clinical trials, which will be a much faster and less labor-intensive way compared to the development of innovative drugs. An example is CoQ10, whose protective for kidney role was demonstrated in type 2 diabetes: CoQ10 stabilized ATP production, inhibited the production of mitochondrial hydrogen peroxide, and restored the mitochondrial membrane potential. ⁵⁰ CoQ10 has been included as the main drug in phase III clinical trials for the treatment of Parkinson’s disease. 5 ⁵¹ and mitochondrial diseases. ⁵² In addition to affecting oxidative stress, possible therapeutic strategies for CKD include modeling mitochondrial dynamics (activation of mitochondrial biogenesis and attenuation of mitochondrial division), restoration of the ETC in mitochondria and inhibitors of the opening of the mitochondrial permeability pore to prevent triggering apoptosis. ²⁹ An important issue that needs to be addressed also remains the monitoring of the mitochondrial state in kidney cells to assess the severity of the disease. In this regard, the correlation, if any, between the prevalence of mitochondrial dysfunction and the clinical manifestations of CKD should be explored. Understanding this relationship may provide a new impetus for studying the role of mitochondria in the progression of chronic diseases and answer the question of whether mitochondrial dysfunction is primarily a consequence of the development of the disease or the cause of the deterioration of the clinical condition of patients with CKD. It is also important to study the role of various oxidized reactive organic compounds formed as a result of increased oxidative stress in damage to the structures of kidney cells. Identification of the most aggressive compounds will allow developing their inhibitors that will help to stop the destructive oxidative reactions occurring in kidney cells. Biomarkers of oxidative stress, which can be obtained non-invasively from saliva, urine or blood, are a promising object of future research. ⁵³ Groups of such markers may include advanced oxidation protein products, malondialdehyde and superoxide dismutase. ⁵³ Given the importance of changes in lipid metabolism in the onset of mitochondrial dysfunction and further development of the pathological condition in CKD, attention should be paid to the level of expression and activity of enzymes involved in these processes. This will potentially contribute to the identification of new therapeutic targets and subsequently the development of new therapeutic agents aimed at normalizing lipid metabolism in the kidneys. A promising solution for the treatment of CKD may be the use of mitochondria-targeted antioxidants, both natural and artificial. ⁵⁴

Conclusions

CKD is a complex multifactorial disease, many points in the pathogenesis of which are still unclear. Given the high importance of mitochondria for the proper functioning of the kidneys in general, and in particular for the cells of the proximal tubules of the kidneys, the onset of mitochondrial dysfunction may be a highly probable event in the pathogenesis of various kidney diseases, including CKD. Indeed, the presence of mitochondrial dysfunction has been demonstrated in many models of CKD. Here, we hypothesize that mitochondrial dysfunction in CKD may be based on causes associated withDN, and more specifically, with the lipotoxicity caused by it, disruption of mitochondrial dynamics, ischemia-reperfusion injury to the kidneys, and nephrotoxic effects of chemotherapy drugs. The occurrence of mitochondrial dysfunction, on the one hand, leads to energy deficiency of kidney cells and their subsequent death, and, on the other hand, to the development of oxidative stress, which, in addition to enhancing mitochondrial dysfunction and inducing apoptosis, causes the development of chronic inflammation in CKD.