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Aparicio-Trejo, O. Mitochondrial Redox Signaling, Kidney Diseases. Encyclopedia. Available online: (accessed on 17 June 2024).
Aparicio-Trejo O. Mitochondrial Redox Signaling, Kidney Diseases. Encyclopedia. Available at: Accessed June 17, 2024.
Aparicio-Trejo, Omar. "Mitochondrial Redox Signaling, Kidney Diseases" Encyclopedia, (accessed June 17, 2024).
Aparicio-Trejo, O. (2021, December 20). Mitochondrial Redox Signaling, Kidney Diseases. In Encyclopedia.
Aparicio-Trejo, Omar. "Mitochondrial Redox Signaling, Kidney Diseases." Encyclopedia. Web. 20 December, 2021.
Mitochondrial Redox Signaling, Kidney Diseases

Redox signaling conveys external and internal signals between redox-sensitive receptors and the downstream effectors of fission machinery. Mitochondrial dynamics require the recruitment of proteins to mitochondria. Indeed, the importation of several proteins to mitochondria depends on proton electrochemical gradient H+created by ETS at the IMM, which is called the proton motive force (PMF).

acute kidney injury (AKI) chronic kidney disease (CKD) tricarboxylic acid (TCA) cycle mitochondrial metabolism mitochondrial redox signaling mitochondrial proteins oxidative phosphorylation (OXPHOS) fatty acid (FA) β-oxidation mitochondrial dynamics biog

1. Introduction

Kidney diseases are a severe health problem that causes high economic costs worldwide in medical attention, emergency, therapies, among others [1][2]. These are divided into acute kidney injury (AKI) and chronic kidney diseases (CKD). AKI encompasses a set of pathologies characterized by the rapid loss of renal function in a short period [3]. AKI is often caused by the use of chemotherapeutics agents such as cisplatin, episodes of renal ischemia/reperfusion (I/R), and exposure to contaminants [4]. AKI is associated with high morbidity and mortality, contributing to CKD development and affecting approximately between 7% and 12% of the world [5]. CKD cause renal fibrosis development [6][7][8]. The latter comprises an unsatisfactory repair process and is the consequence of severe and persistent damage that does not restore organ function [9]. Renal fibrosis, in turn, is one of the principal mechanisms involved in AKI to CKD transition [5].

Mitochondria are responsible for several cell functions such as cell growth, cell survival, and apoptosis induction, playing a significant role in kidney physiology and the development of kidney diseases. Mitochondria also coordinate the biosynthesis of lipids, amino acids, and nucleotides and bioenergetics processes such as tricarboxylic acid (TCA) cycles, electron transport systems (ETSs), and fatty acids (FA) β-oxidation [10]. During these processes, reactive oxygen species (ROS) are produced. Low levels of ROS are needed to regulate cellular signaling, but an excess of ROS induces oxidative stress (OS). OS causes oxidative damage in organelles including mitochondria and biomolecules, such as proteins, lipids, and deoxyribonucleic acid (DNA), which may be conducive to cell death. Indeed, OS is associated with AKI development and its transition to CKD, where mitochondria dysfunction is the principal characteristic of both [11][12]. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in renal mitochondria impairment is not well understood. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.

2. Ox-PTMs Regulate Manganese Superoxide Dismutase (Mn-SOD) in Kidney Injury

Mn-SOD is in the mitochondrial matrix, while copper/zinc-SOD (Cu/Zn-SOD) is in the space of the inner mitochondrial membrane (IMM) and IMS. These two enzymes catalyze the dismutation of O 2• − to H 2O 2 in the mitochondrial matrix and IMS, respectively [13]. This dismutation is crucial to avoid the O 2• − -induced ferric iron (Fe 3+ ) to ferrous iron (Fe 2+ ) reduction in Fe-S clusters of critical enzymes such as aconitase (Acn). The latter leads to the release of Fe 2+ and the inactivation of these enzymes [14]. During Fenton/Haber–Weiss reaction, Fe 2+ reacts with H 2O 2 to produce a highly reactive ROS, hydroxyl radical ( • OH), so the regulation of O 2•− is essential to maintain mitochondrial homeostasis. Moreover, O 2•− overproduction, directly and indirectly, leads to the inactivation of Mn-SOD, promoting mitochondrial dysfunction. For instance, O 2•− can react with • NO to produce peroxynitrite (ONOO − ), and ONOO − can induce Mn-SOD deactivation via nitration of Tyr34 residue in its active site [15].

Mn-SOD can also be S-glutathionylated in Cys 196, avoiding irreversible oxidation of SH. Renal I/R injury induces O 2•− and ONOO − production [16], increasing nitration levels of mitochondrial proteins such as Mn-SOD and cytochrome c (cyt c), inactivating them and inducing OS and mitochondrial dysfunction [17][18][19][20]. Likewise, in folic-acid-induced renal damage, Mn-SOD activity reduction in isolated mitochondria is related to decreased mitochondrial S-glutathionylation [21], making it more susceptible to nitration. Moreover, in human renal transplants and experimental rat models of chronic renal nephropathy, there are elevated levels of ONOO − [18].

In DKD, mitochondrial OS reduces Mn-SOD enzyme activity due to Tyr nitration of this enzyme. Interestingly, the use of resveratrol, a potent antioxidant, reduces OS and Tyr nitration of Mn-SOD, preserving Mn-SOD activity. Moreover, kidneys of mice treated with streptozotocin to induced diabetic nephropathy (DN) show nitration in Mn-SOD Tyr 34, which results in a decrease of Mn-SOD. However, antagonists of thromboxane A2 receptors reduce diabetes-induced renal injury, which is associated with Mn-SOS Tyr nitration reduction [22].

In models of hypertension-related kidney injury, where hypertension is induced by angiotensin II (Ang II), the production of O 2•− is promoted through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) [23]. In these models, Mn-SOD activity deactivation is also associated with Tyr nitration, inducing OS [24]. Moreover, spontaneously hypertensive rats treated with N(G)-nitro-L-arginine-methyl ester (L-NAME), a potent nitric oxide synthase (NOS) inhibitor, reduce nitration of Mn-SOD, preserving its activity [25].

3. Mitochondrial Metabolism, ROS, and OS in Kidney Diseases

In summary, defective FA β-oxidation is observed in kidney diseases from early times, promoted through decreased mRNA expression and downregulation in the activity and levels of the proteins involved in this process and ETS activity reduction (discussed below). Later, the overexpression of CD36 contributes to lipid accumulation and the activation of mechanisms that lead to the fibrotic process. However, other factors contribute to the impairment of β-oxidation.

On the other hand, Tan et al. [26] showed by transcriptomic analysis in diabetic mice that mitochondrial FA β-oxidation is downregulated. This downregulation is attributed to the overexpression of the C5 substrate of the complement system receptor 1 (C5aR1). Thus, C5aR1 is implicated in lipids metabolism in diabetes [27]. C5aR1 is also upregulated in kidney diseases, producing FA β-oxidation impairment in DN [26]. In addition, C5aR1 upregulation disrupts mitochondrial respiration, generating high levels of ROS. These results showed that C5aR1-induced ROS overproduction alters FA metabolism in DN.

TCA cycle dysfunction might be attributed to ROS alterations. In vitro studies have postulated that high glucose oxidation rates lead to the excessive production of electron donors from the TCA cycle. As a consequence, ETS becomes overloaded, promoting O 2• − overproduction [28]. In line with this, podocytes treated with high glucose levels have high ROS levels, and the treatment with mitoTEMPO decreases them [29], suggesting that ROS are specifically delivered from mitochondria. Controversially, the determination of mtROS in the diabetic mouse model shows that it is reduced [30]. Further studies in vivo are needed to elucidate the mtROS overproduction-induced TCA cycle dysfunction in DN.

In the kidney, TCA cycle enzymes can be sulfenylated or S-glutathionylated. For example, Acn can be reversibly inactivated by the oxidation of the sulfhydryl group by O 2• − and H 2O 2. However, if OS persists, Acn can be irreversibly deactivated by the disruption of the 4Fe-4S group [31]. In AKI induced by folic acid, mitochondrial Acn activity decreases, and the pre-treatment with NAC prevents it [21], suggesting that ROS promote the deactivation of Acn. In addition, the relation between Acn and citrate synthase diminishes, supporting the idea that decreasing in Acn activity is related to OS [21]. Moreover, Mapuskar et al. [32] reported that the persistent increase of O 2•− decreases Acn and citrate synthase activity in cisplatin-induced kidney injury, of which the effects are ameliorated by SOD mimetic avasopasem manganese (GC4419) treatment. It is reported that in the AKI phase, Acn and citrate synthase activities do not show changes, suggesting that high levels of ROS are required for their inactivation in this model [32]. The latter is demonstrated due to the fact that high levels of ROS are more evident in cisplatin-induced CKD [32].

4. ROS Induce Uncoupling Proteins (UCPs) Dysregulation in Kidney Diseases

UCPs are proton transporters (H + ), which move H + from the IMM into the mitochondrial matrix. These transporters are localized in the IMM and dissipate the proton gradient from the mitochondrial matrix into the IMS [33]. mtROS induce UCP2 activation, decreasing the proton gradient and preventing mtROS overproduction [33].

It has been shown that UCP2 deletion aggravates tubular injury in the I/R model by inducing ROS overproduction, supporting the importance of these transporters in ROS dissipation [34]. Moreover, the UCP2 inhibition worsens the damage caused by lipopolysaccharide (LPS), increasing apoptosis in TECs [35]. In CKD, Jian et al. [36] showed that in renal tubular cells (RTCs), the expression of UCP2 is induced three days after obstruction and continues after seven days, avoiding UUO-induced fibrosis. It suggests that UCP2 is crucial to avert fibrosis development induced by ROS in UUO.

Although UCP1 is commonly found in mitochondria from brown adipose tissue, it is expressed in the kidney. For instance, in AKI models induced by cisplatin or I/R, Jia et al. [37] found that UCP1 is upregulated in renal TECs and its presence is related to OS suppression. Chouchani et al. [38] showed that mtROS alter the redox status of UCP1 by inducing its sulfenylation in Cys 253, promoting UCP1 activity.


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