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Review
. 2022 Dec 25;12(1):88.
doi: 10.3390/cells12010088.

Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease

Hsin-Jung Ho  1 , Hitoshi Shirakawa  2   3
Affiliations
Review

Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease

Hsin-Jung Ho et al. Cells. .

Abstract

The kidney contains many mitochondria that generate ATP to provide energy for cellular processes. Oxidative stress injury can be caused by impaired mitochondria with excessive levels of reactive oxygen species. Accumulating evidence has indicated a relationship between oxidative stress and kidney diseases, and revealed new insights into mitochondria-targeted therapeutics for renal injury. Improving mitochondrial homeostasis, increasing mitochondrial biogenesis, and balancing mitochondrial turnover has the potential to protect renal function against oxidative stress. Although there are some reviews that addressed this issue, the articles summarizing the relationship between mitochondria-targeted effects and the risk factors of renal failure are still few. In this review, we integrate recent studies on oxidative stress and mitochondrial function in kidney diseases, especially chronic kidney disease. We organized the causes and risk factors of oxidative stress in the kidneys based in their mitochondria-targeted effects. This review also listed the possible candidates for clinical therapeutics of kidney diseases by modulating mitochondrial function.

Keywords: chronic kidney disease; mitochondrial homeostasis; mitochondrial turnover; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nephron structure in the kidney. The nephron is the functional unit of the kidney. The glomerulus is the filtering unit located at the beginning of a nephron. Glomerular cells comprise endothelial cells, mesangial cells, podocytes and epithelial cells. Oxidative stress likely causes dysfunction of these cells, leading to renal damage.
Figure 2
Figure 2
Mitochondria-targeted therapeutics for oxidative damage. Mitochondria produce energy via the oxidative phosphorylation process in the electron transport chain (ETC) present in the mitochondrial membrane. Mitochondrial membrane potential (MMP) plays a key role in mitochondrial homeostasis. To maintain mitochondrial function, fusion reduces stress and enhances integrity by sharing the contents as a form of complementation. Fission segregates the damaged region of mitochondria. Mitochondrial biogenesis is the process that regulates the number of healthy mitochondria, resulting in increased ATP production. Mitophagy is the selective process for removing the dysfunctional mitochondria. The complicated processes can control mitochondrial quality and cell metabolism, which may also provide possible therapeutic targets for oxidative damage.
Figure 3
Figure 3
Regulation of mitochondrial permeability transition pore (mPTP) for maintaining mitochondria homeostasis. mPTP is a protein complex present between the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM). The mPTP is composed of a voltage-dependent anion channel (VDAC) and adenine nucleoside translocator protein (ANT) that act to regulate MMP for mitochondria homeostasis. Under pathophysiological conditions, excessive Ca2+ and ROS induce mPTP opening and cause mitochondrial-related apoptosis.
Figure 4
Figure 4
Mitochondrial antioxidant system and OXPHOS. (A) Mitochondrial antioxidants and ROS production. Mitochondria are the major source of superoxide (O2˙−) in aerobic organisms. ETC generate ATP and results in O2˙− production, which is converted to hydrogen peroxide (H2O2) by manganese-superoxide dismutase (MnSOD), and then converted to H2O by glutathione peroxidase (GPx). Uncoupling protein-2 (UCP2) also plays a key role in the control of intracellular oxidative stress. (B) Mitochondrial ETC and OXPHOS. Electrons (e−) are transferred from reduced nicotinamide adenine dinucleotide (NADH) to oxidized form (NAD+) in complex I (CI) or from flavin adenine dinucleotide (FADH2)-containing enzymes complex II (CII) to reduce CoQ10 (Q). The electrons are then transferred to complex III (CIII, bc1 complex) and cyt c. Finally, H2 reacts with O2 to yield H2O in complex IV (CIV). Complex V (CV, ATP synthase) synthesizes ATP from ADP, which is driven from the proton (H+) gradient (produced by CI, CIII and CIV). In addition, the NADH and FADH2 for OXPHOS are produced by both fatty acid β-oxidation and the tricarboxylic acid (TCA) cycle. Acetyl-CoA is generated from fatty acids (β-oxidation), amino acids or pyruvate (glycolysis) for initial mitochondrial TCA cycle reactivation.
Figure 5
Figure 5
Molecular mechanisms of mitochondrial turnover. (A) Mitochondrial biogenesis. Nuclear peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) activates its target genes Nrf1/2. Transcription factor A, mitochondrial (TFAM) promotes mtDNA transcription and replication to generate new mitochondria. (B) Mitochondrial fusion/fission. Mitochondria are highly dynamic organelles that frequently fuse and divide. Mitochondrial fusion is mediated by mitofusins (Mfns) and optic atrophy protein 1 (OPA1). Mitochondrial fission is mediated by dynamin-related proteins and mitochondrial fission 1 protein (FIS1). (C) Mitophagy. Mitochondrial quality control systems are essential for the maintenance of functional mitochondria. Mitophagy is the selective degradation of mitochondria by autophagy. In mitophagy, the target mitochondria are recognized by the autophagosomes and delivered to the lysosome for degradation.
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The authors sincerely appreciate the funding from a Grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) to H.-J.H. (#22K1174602).