Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease: From Molecular Mechanisms to Biomarkers and Targeted Therapies

1. Introduction

The kidney is among the most metabolically active organs in the human body, characterized by high oxygen consumption and an exceptionally dense mitochondrial network that supports its complex physiological functions. In fact, the renal cortex—particularly the proximal tubular epithelium—contains one of the highest mitochondrial densities among mammalian tissues, surpassed only by the myocardium [1]. This remarkable abundance reflects the enormous bioenergetic requirements associated with maintaining renal homeostasis, including glomerular filtration, electrolyte balance, acid–base regulation, and active reabsorption of solutes and water. Approximately 180 liters of glomerular filtrate are processed by the kidneys daily, and the majority of this filtrate is reabsorbed in the proximal tubules through energy-dependent transport mechanisms that rely heavily on mitochondrial adenosine triphosphate (ATP) production [1,2,3].

Mitochondria generate ATP primarily through oxidative phosphorylation (OXPHOS), a process driven by the mitochondrial electron transport chain (ETC) located within the inner mitochondrial membrane [1,4,5]. Electrons derived from metabolic substrates are transferred through ETC complexes I–IV, ultimately reducing oxygen to water while generating a proton gradient that powers ATP synthesis. While this system is highly efficient, it also represents a major source of reactive oxygen species (ROS), which are generated as unavoidable byproducts of electron leakage from ETC complexes—particularly complexes I and III [1,6]. Under physiological conditions, low levels of ROS function as signaling molecules that regulate cellular processes such as proliferation, differentiation, and stress responses. However, excessive ROS production or impaired antioxidant defenses disrupt cellular redox homeostasis, leading to oxidative stress and damage to lipids, proteins, and nucleic acids [7,8,9].

Chronic kidney disease (CKD) is increasingly recognized as a disorder characterized by profound disturbances in mitochondrial function and redox balance. Affecting more than 750 million individuals worldwide, CKD represents a significant public health challenge and is associated with increased cardiovascular risk, reduced quality of life, and high healthcare costs [10]. Although CKD arises from diverse etiologies—including diabetes, hypertension, autoimmune disorders, and genetic abnormalities—mounting evidence suggests that mitochondrial dysfunction and oxidative stress represent common downstream pathways driving disease progression [8,11,12,13].

Mitochondrial dysfunction in renal cells manifests through multiple mechanisms, including impaired oxidative phosphorylation, mitochondrial DNA (mtDNA) damage, altered mitochondrial dynamics, and defective mitochondrial quality control pathways [6,14,15]. These alterations lead to decreased ATP production, increased ROS generation, and activation of inflammatory and fibrotic signaling pathways that contribute to tubular injury and progressive loss of renal function [6,8,14]. In addition, damaged mitochondria can release mtDNA and other mitochondrial components into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways such as Toll-like receptor 9 (TLR9) and the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling cascade, further amplifying inflammatory responses in the kidney [16,17,18].

Another critical aspect of mitochondrial homeostasis in the kidney involves mitochondrial quality control (MQC), a coordinated network of processes that maintain mitochondrial integrity and functionality. These processes include mitochondrial dynamics (fusion and fission), mitophagy (the selective removal of damaged mitochondria), and mitochondrial biogenesis [3,6,19]. Disruption of MQC leads to the accumulation of dysfunctional mitochondria that generate excessive ROS and contribute to cellular injury, inflammation, and fibrosis—hallmarks of CKD progression [6,8,11,20].

Recent advances in molecular nephrology have revealed that mitochondrial dysfunction is not only a consequence of renal injury but also a central driver of disease initiation and progression. Emerging pathogenic mechanisms—including ferroptosis, epigenetic regulation of mitochondrial genes, and metabolic reprogramming—have further expanded our understanding of how oxidative stress and mitochondrial alterations contribute to renal pathology [4,14,15,21,22]. Moreover, novel therapeutic strategies targeting mitochondrial pathways are currently being investigated, raising the possibility that restoring mitochondrial homeostasis may represent a promising approach for preventing or slowing CKD progression [4,14,23,24].

This review aims to provide a comprehensive overview of the molecular mechanisms linking oxidative stress and mitochondrial dysfunction to chronic kidney disease. We discuss the major sources of oxidative stress in renal tissue, examine the role of mitochondrial quality control pathways, and explore emerging pathogenic mechanisms such as ferroptosis and epigenetic regulation. In addition, we review current and potential therapeutic strategies targeting mitochondrial dysfunction and highlight the clinical relevance of redox biomarkers for improving diagnosis, risk stratification, and personalized treatment of CKD.

2. Primary Sources of Oxidative Stress in the Renal Parenchyma

Oxidative stress represents a fundamental pathogenic mechanism in chronic kidney disease and is characterized by an imbalance between the production of reactive oxygen species (ROS) and the capacity of cellular antioxidant systems to neutralize them. In the kidney, several cellular and molecular processes contribute to ROS generation, including mitochondrial dysfunction, activation of NADPH oxidases, hormonal signaling pathways such as the renin–angiotensin–aldosterone system (RAAS), and the accumulation of uremic toxins associated with dysbiosis of the gut microbiota. These processes interact to create a complex network of redox dysregulation that promotes inflammation, cellular injury, and progressive renal fibrosis (Figure 1) [7,8,14,25].

2.1. Mitochondrial Electron Transport Chain Dysfunction and Superoxide Leakage

Mitochondria represent the primary endogenous source of reactive oxygen species in most mammalian cells. During oxidative phosphorylation (OXPHOS), electrons derived from metabolic substrates are transferred through the mitochondrial electron transport chain, which consists of five multiprotein complexes embedded within the inner mitochondrial membrane. Although the ETC is designed to efficiently transfer electrons to molecular oxygen, a small proportion of electrons prematurely escape the chain and react with oxygen to form the superoxide radical (O₂•⁻) [1,26,27].

Under physiological conditions, mitochondrial ROS production is tightly controlled by antioxidant defense systems such as superoxide dismutases (SODs), catalase, glutathione peroxidase, and peroxiredoxins [23,28,29,30]. However, pathological conditions associated with CKD—such as hyperglycemia, lipid overload, hypoxia, and inflammation—can impair ETC function and increase electron leakage, resulting in excessive ROS production. Complexes I and III are considered the primary sites of superoxide generation, and structural or functional alterations in these complexes have been frequently observed in experimental models of kidney disease [8,15,26,27,31].

In proximal tubular epithelial cells, mitochondrial dysfunction is particularly detrimental due to their heavy reliance on fatty acid oxidation (FAO) as a primary energy source. Disruption of FAO leads to the accumulation of lipid intermediates, including long-chain acylcarnitines, which interfere with mitochondrial metabolism and further increase ROS production. This process contributes to lipotoxicity, mitochondrial fragmentation, and the progressive decline of cellular bioenergetic capacity [32]. In addition, oxidative damage to mitochondrial DNA can impair the synthesis of essential ETC proteins encoded by the mitochondrial genome, further compromising mitochondrial respiration and establishing a self-perpetuating cycle of oxidative stress and mitochondrial dysfunction [16,31].

Mitochondrial oxidative stress also plays a critical role in acute kidney injury (AKI), where early mitochondrial damage leads to ATP depletion, tubular cell death, and inflammation. In experimental models of ischemia–reperfusion injury and nephrotoxic damage, increased mitochondrial ROS production has been shown to trigger activation of inflammatory pathways such as the NLRP3 inflammasome and promote the transition from AKI to CKD [16,33,34,35,36,37,38,39].

2.2. NADPH Oxidase Signaling: The Central Role of NOX4

While mitochondria generate ROS as byproducts of metabolism, the NADPH oxidase (NOX) family of enzymes produces ROS as its primary biological function. Among the seven NOX isoforms identified in mammals, NOX4 is the predominant isoform expressed in renal tissue and is particularly abundant in tubular epithelial cells, podocytes, and endothelial cells [40,41,42,43,44].

Unlike other NOX isoforms that primarily generate superoxide, NOX4 predominantly produces hydrogen peroxide (H₂O₂), a relatively stable ROS that can diffuse across cellular compartments and participate in redox signaling. Under physiological conditions, NOX4-derived ROS contribute to cellular signaling pathways involved in differentiation and metabolic adaptation. However, chronic activation of NOX4 has been implicated in the pathogenesis of multiple kidney diseases, including diabetic kidney disease, hypertensive nephropathy, and renal fibrosis [41,42,43,44,45,46,47].

In diabetic kidney disease, hyperglycemia and advanced glycation end products stimulate NOX4 expression in podocytes and mesangial cells, leading to increased ROS production and activation of pro-fibrotic signaling pathways such as transforming growth factor-β (TGF-β) signaling. Increased NOX4 activity has also been linked to podocyte apoptosis, glomerulosclerosis, and albuminuria in experimental models of diabetic nephropathy [42,48,49,50,51,52].

Recent studies have identified the SH3YL1 protein as an important cytosolic activator that interacts with NOX4 to enhance ROS generation in renal cells [4]. Disruption of the SH3YL1–NOX4 interaction has been shown to reduce oxidative stress and attenuate renal fibrosis in experimental models, highlighting this signaling axis as a potential therapeutic target. Furthermore, several pharmacological compounds—including polyphenols and AMPK activators—have been shown to suppress NOX4 expression and mitigate oxidative stress in diabetic kidney disease [12,53,54,55].

2.3. RAAS Activation and Redox Crosstalk

The renin–angiotensin–aldosterone system (RAAS) plays a central role in regulating blood pressure, fluid balance, and renal hemodynamics. However, chronic activation of RAAS is also a major contributor to oxidative stress and inflammation in CKD. Angiotensin II (Ang II), the principal effector peptide of RAAS, exerts multiple deleterious effects on renal tissue through activation of the angiotensin II type 1 receptor (AT₁R) [40,44,56].

Binding of Ang II to AT₁R stimulates the activation of NADPH oxidases, particularly NOX4, leading to increased ROS production and oxidative damage in renal cells. This ROS generation initiates a cascade of signaling events that activate transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), promoting the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. As a result, immune cells—including macrophages and T lymphocytes—are recruited to the kidney, further amplifying inflammatory responses and promoting tissue injury [40,44,56].

Moreover, Ang II-induced ROS production can impair mitochondrial function by damaging mitochondrial DNA, disrupting mitochondrial membrane potential, and promoting mitochondrial fragmentation. This interaction between RAAS signaling and mitochondrial dysfunction establishes a feedback loop in which oxidative stress perpetuates inflammation and fibrosis, ultimately contributing to progressive renal damage [8,11,31,40,44,57,58].

2.4. The Gut–Kidney Axis and Uremic Toxins

In addition to intrinsic renal sources of oxidative stress, increasing attention has been directed toward the role of the gut–kidney axis in the pathogenesis of chronic kidney disease. Alterations in intestinal microbiota composition and metabolism—collectively referred to as dysbiosis—contribute to the generation and systemic accumulation of uremic toxins that exacerbate oxidative stress and inflammation in CKD [25,59,60,61,62].

In patients with impaired renal function, the reduced clearance of microbial metabolites leads to the accumulation of several protein-bound uremic toxins, among which indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are the most extensively studied. These metabolites originate from the bacterial metabolism of dietary amino acids such as tryptophan and tyrosine and undergo hepatic conjugation before entering systemic circulation. Because of their strong binding affinity to albumin, these toxins are poorly removed by conventional dialysis and progressively accumulate as kidney function declines [60,61,63,64,65].

Indoxyl sulfate has been identified as a potent inducer of oxidative stress in renal tubular epithelial cells and vascular endothelial cells. Mechanistically, IS stimulates ROS production through the activation of NADPH oxidases, particularly NOX4, and enhances mitochondrial oxidative stress. Moreover, IS interferes with endogenous antioxidant defense systems by suppressing the activity of nuclear factor erythroid 2–related factor 2 (Nrf2), a transcription factor that regulates the expression of numerous antioxidant and detoxification enzymes [63,66]. The inhibition of Nrf2 signaling results in decreased expression of protective proteins such as heme oxygenase-1 (HO-1), glutathione peroxidase, and superoxide dismutase, thereby exacerbating oxidative damage within renal tissue [28,29,66,67,68].

Beyond its direct pro-oxidant effects, indoxyl sulfate also promotes inflammatory signaling pathways that contribute to renal fibrosis. Activation of the aryl hydrocarbon receptor (AhR) by IS triggers downstream signaling cascades that stimulate the production of pro-inflammatory cytokines and profibrotic mediators, including transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF). These processes accelerate tubulointerstitial fibrosis, which represents a key determinant of CKD progression [59,63,69].

The systemic consequences of gut-derived uremic toxins extend beyond the kidney. Elevated circulating levels of IS and pCS have been strongly associated with endothelial dysfunction, vascular calcification, and increased cardiovascular risk in CKD patients. Oxidative stress induced by these toxins contributes to mitochondrial damage in vascular cells, thereby linking renal dysfunction with the heightened cardiovascular morbidity observed in CKD populations [56,59,63,70,71].

Importantly, therapeutic strategies aimed at modulating the gut microbiota—including dietary interventions, probiotics, prebiotics, and oral adsorbents—are currently being investigated as potential approaches to reduce uremic toxin burden and mitigate oxidative stress in CKD. Although clinical evidence remains limited, these strategies highlight the growing recognition of the gut–kidney axis as an important contributor to oxidative stress and mitochondrial dysfunction in chronic kidney disease [59,61,69,72].

3. Mitochondrial Quality Control (MQC) Failure

Mitochondrial homeostasis is maintained by a highly coordinated network of processes collectively referred to as mitochondrial quality control (MQC). These mechanisms ensure the preservation of mitochondrial integrity and functionality through the dynamic regulation of mitochondrial morphology, selective removal of damaged organelles, and synthesis of new mitochondria. The MQC system consists primarily of three interconnected processes: mitochondrial dynamics (fusion and fission), mitophagy, and mitochondrial biogenesis [6,19,73].

In the healthy kidney, these processes work in concert to maintain an efficient mitochondrial network capable of meeting the high metabolic demands of renal tubular cells. However, in chronic kidney disease, multiple stressors—including oxidative stress, metabolic dysregulation, and inflammatory signaling—disrupt MQC pathways, leading to the accumulation of dysfunctional mitochondria. These damaged organelles generate excessive reactive oxygen species, impair ATP production, and activate apoptotic and inflammatory pathways that contribute to progressive renal injury [4,8,11,19,31,74].

Recent studies have highlighted the central importance of MQC dysfunction in both acute kidney injury (AKI) and CKD. In AKI models, early mitochondrial fragmentation and impaired mitophagy lead to rapid ATP depletion and tubular cell death. When mitochondrial damage persists or repair mechanisms fail, maladaptive responses can promote the transition from AKI to CKD through chronic inflammation and fibrosis (Figure 2) [6,33,35,36,38].

3.1. Mitochondrial Dynamics: The Balance Between Fusion and Fission

Mitochondria are highly dynamic organelles that continuously undergo cycles of fusion and fission. This dynamic remodeling allows mitochondria to adapt to changing metabolic conditions, maintain mitochondrial DNA integrity, and segregate damaged mitochondrial components for degradation [75,76,77,78,79,80,81].

Mitochondrial fusion involves the merging of adjacent mitochondria, enabling the exchange of mitochondrial DNA, proteins, and metabolites. This process helps dilute damaged mitochondrial components and maintain mitochondrial functionality. Fusion is primarily mediated by three key proteins: mitofusin-1 (MFN1), mitofusin-2 (MFN2), and optic atrophy protein 1 (OPA1). MFN1 and MFN2 regulate the fusion of the outer mitochondrial membrane, whereas OPA1 mediates fusion of the inner mitochondrial membrane [75,76,77,78,79,80,81].

In contrast, mitochondrial fission involves the division of mitochondria into smaller organelles. This process is essential for mitochondrial distribution during cell division and for isolating damaged mitochondrial segments that require removal by mitophagy. The central mediator of mitochondrial fission is dynamin-related protein 1 (Drp1), a cytosolic GTPase that translocates to the mitochondrial outer membrane where it interacts with receptor proteins such as Fis1, Mff, and MiD49/51 to constrict and divide the mitochondrial membrane [75,77,78,81,82].

The activity of Drp1 is tightly regulated by post-translational modifications, particularly phosphorylation at specific serine residues. Phosphorylation of Drp1 at serine 616 (p-Drp1S616) promotes mitochondrial fission and has been associated with mitochondrial fragmentation and apoptosis. Conversely, phosphorylation at serine 637 (p-Drp1S637) inhibits Drp1 activity and favors mitochondrial elongation [75,82,83,84,85].

In CKD, the balance between mitochondrial fusion and fission is frequently disrupted, resulting in excessive mitochondrial fragmentation. Elevated levels of p-Drp1S616 and reduced expression of fusion proteins such as MFN2 and OPA1 have been reported in various models of renal injury. This imbalance leads to fragmented mitochondria that exhibit impaired respiratory capacity and increased ROS production, ultimately contributing to tubular cell apoptosis and renal fibrosis [8,11,75,82,83].

Furthermore, excessive mitochondrial fission has been linked to the activation of pro-fibrotic signaling pathways in kidney disease. Mitochondrial fragmentation promotes the release of cytochrome c and other pro-apoptotic factors, initiating the intrinsic apoptotic pathway and amplifying cellular injury. In addition, fragmented mitochondria produce higher levels of ROS, further exacerbating oxidative stress and inflammatory responses within renal tissue.

3.2. Mitophagy Pathways: The PINK1/Parkin Cascade

Mitophagy is the selective degradation of damaged or dysfunctional mitochondria through the autophagy–lysosome pathway. This process represents a critical defense mechanism against mitochondrial dysfunction by removing ROS-producing mitochondria before they can cause irreversible cellular damage [6,73,86,87,88,89].

Among the various mitophagy pathways described in mammalian cells, the PINK1/Parkin-mediated pathway is the most extensively characterized. Under normal conditions, PTEN-induced kinase 1 (PINK1) is continuously imported into healthy mitochondria and rapidly degraded. However, when mitochondria lose their membrane potential—a hallmark of mitochondrial damage—PINK1 accumulates on the outer mitochondrial membrane [87,90,91].

The accumulation of PINK1 triggers a series of molecular events that initiate mitophagy. PINK1 undergoes autophosphorylation and subsequently phosphorylates ubiquitin molecules and the E3 ubiquitin ligase Parkin. Activated Parkin translocates from the cytosol to the damaged mitochondria, where it ubiquitinates numerous outer mitochondrial membrane proteins, including voltage-dependent anion channels (VDACs) and mitofusins [87,90,91].

These ubiquitin tags serve as signals for the recruitment of autophagy receptors such as optineurin (OPTN) and nuclear dot protein 52 (NDP52). These receptors interact with microtubule-associated protein light chain 3 (LC3) on the surface of forming autophagosomes, enabling the engulfment of damaged mitochondria and their subsequent degradation within lysosomes [6,73,86,88,91].

Mitophagy plays a protective role in kidney injury by limiting mitochondrial ROS production and preventing activation of inflammatory pathways. Experimental studies have demonstrated that genetic deletion of PINK1 or Parkin exacerbates renal injury in models of ischemia–reperfusion and cisplatin-induced nephrotoxicity. In these models, impaired mitophagy leads to the accumulation of dysfunctional mitochondria, increased oxidative stress, and enhanced activation of inflammatory pathways such as the NLRP3 inflammasome [15,33,37,86,92].

In addition to the PINK1/Parkin pathway, receptor-mediated mitophagy pathways have also been described. Proteins such as BNIP3, NIX, and FUNDC1 contain LC3-interacting regions (LIRs) that allow them to directly recruit autophagosomes without requiring ubiquitination. These pathways are particularly important during hypoxic stress and have been implicated in renal ischemia and diabetic nephropathy [6,73,86,88,89].

Despite its protective role in acute injury, dysregulated mitophagy may contribute to chronic kidney disease when mitochondrial clearance becomes insufficient or maladaptive. Clinical studies have demonstrated that impaired mitophagy correlates with declining glomerular filtration rate (GFR) and increased renal fibrosis in CKD patients, suggesting that defective mitochondrial turnover represents a critical mechanism of disease progression [11,15,19,86].

3.3. Mitochondrial Biogenesis and the PGC-1α Signaling Axis

While mitophagy removes damaged mitochondria, mitochondrial biogenesis replenishes the mitochondrial pool by generating new organelles. This process is primarily regulated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), which orchestrates the expression of nuclear genes encoding mitochondrial proteins [93,94,95].

PGC-1α interacts with several transcription factors, including nuclear respiratory factors 1 and 2 (NRF1 and NRF2), to stimulate the transcription of genes required for mitochondrial respiration, fatty acid oxidation, and oxidative metabolism. One of the key downstream targets of PGC-1α is mitochondrial transcription factor A (TFAM), which is essential for mitochondrial DNA replication and transcription [93,94,95,96].

In healthy renal tissue, PGC-1α plays a central role in maintaining mitochondrial abundance and metabolic flexibility. However, in CKD, PGC-1α expression is often markedly reduced due to metabolic stress, inflammation, and epigenetic modifications. Reduced PGC-1α signaling leads to impaired mitochondrial biogenesis, decreased mitochondrial mass, and diminished ATP production [8,11,93].

Sirtuin proteins, particularly SIRT1 and SIRT3, are important regulators of PGC-1α activity. These NAD⁺-dependent deacetylases enhance PGC-1α function and promote mitochondrial biogenesis under conditions of metabolic stress. However, reduced sirtuin activity in CKD—often associated with metabolic syndrome and aging—contributes to mitochondrial dysfunction and impaired cellular metabolism [12,93,97,98,99,100].

The combined failure of mitochondrial dynamics, mitophagy, and biogenesis ultimately results in the accumulation of dysfunctional mitochondria that produce excessive ROS and contribute to progressive renal injury. Consequently, restoring mitochondrial quality control has emerged as a promising therapeutic strategy for preventing CKD progression and improving renal outcomes [6,19,93].

4. Emerging Pathogenic Axes in Renal Pathology

Beyond classical oxidative stress pathways, recent advances in molecular nephrology have uncovered several additional mechanisms that connect mitochondrial dysfunction to renal injury. Among these, ferroptosis, epigenetic regulation of mitochondrial genes, and non-coding RNA signaling have emerged as critical contributors to oxidative stress amplification and disease progression in chronic kidney disease (CKD). These mechanisms integrate metabolic disturbances, mitochondrial dysfunction, and inflammatory signaling, forming complex pathogenic networks that drive tubular injury and fibrosis [6,31].

4.1. Ferroptosis: Iron-Dependent Lipid Peroxidation

Ferroptosis is a recently described form of regulated cell death that is mechanistically distinct from apoptosis, necrosis, and autophagy. It is characterized by the iron-dependent accumulation of lipid peroxides that ultimately leads to catastrophic membrane damage and cell death. Ferroptosis has gained increasing attention in kidney research due to its involvement in both acute kidney injury (AKI) and chronic kidney disease progression [6,101,102,103,104,105,106].

At the biochemical level, ferroptosis is driven by uncontrolled lipid peroxidation reactions that occur when cellular antioxidant defenses are overwhelmed. Iron plays a central role in this process through the Fenton reaction, in which ferrous iron (Fe²⁺) reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals [101,104,105,107,108,109]:

Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH•

These radicals initiate lipid peroxidation by attacking polyunsaturated fatty acids (PUFAs) within cellular membranes, leading to the formation of lipid hydroperoxides and membrane destabilization [104,105,106,109].

One of the key enzymes involved in ferroptosis is acyl-CoA synthetase long-chain family member 4 (ACSL4), which promotes the incorporation of polyunsaturated fatty acids such as arachidonic acid into membrane phospholipids. These lipids serve as substrates for lipid peroxidation, thereby sensitizing cells to ferroptotic death [6,104,106,110,111]. Increased ACSL4 expression has been observed in several models of renal injury, suggesting that enhanced lipid remodeling contributes to ferroptosis susceptibility in kidney disease [102,105,112].

The primary defense against ferroptosis is mediated by glutathione peroxidase 4 (GPX4), a selenoprotein that detoxifies lipid hydroperoxides using glutathione (GSH) as a reducing agent. GPX4 converts toxic lipid hydroperoxides into non-toxic lipid alcohols, thereby preventing membrane damage and ferroptotic cell death. Loss of GPX4 activity results in uncontrolled lipid peroxidation and rapid cell death, highlighting its essential role in cellular survival (Figure 3) [6,104,106,113,114,115].

In the kidney, ferroptosis has been implicated in multiple pathological conditions, including ischemia–reperfusion injury, cisplatin-induced nephrotoxicity, and diabetic kidney disease. Experimental studies have demonstrated that inhibition of ferroptosis using pharmacological agents such as ferrostatin-1 or liproxstatin-1 can significantly attenuate renal injury and inflammation, indicating that ferroptosis represents a promising therapeutic target [34,101,102,105,112].

Another important regulatory pathway controlling ferroptosis is the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway. Nrf2 is a transcription factor that regulates the expression of numerous antioxidant and cytoprotective genes, including those involved in glutathione synthesis and iron metabolism. Activation of Nrf2 enhances cellular resistance to ferroptosis by increasing GPX4 expression and restoring redox balance. Conversely, impaired Nrf2 signaling—frequently observed in CKD—facilitates lipid peroxidation and ferroptotic cell death [6,28,29,66,67,68,116].

The close relationship between ferroptosis and mitochondrial dysfunction further highlights the central role of oxidative stress in renal pathology. Mitochondrial ROS production can amplify lipid peroxidation, while mitochondrial iron accumulation can increase susceptibility to ferroptotic injury. These interactions establish ferroptosis as a key mediator linking mitochondrial dysfunction with tubular cell death and progressive renal damage [6,31,103,104,106,107].

4.2. Epigenetic Regulation of Mitochondrial Function

Epigenetic mechanisms have emerged as important regulators of mitochondrial homeostasis and oxidative stress in kidney disease. These mechanisms involve reversible modifications of DNA and histone proteins that influence gene expression without altering the underlying DNA sequence [21,22,117,118,119].

Among the most extensively studied epigenetic modifications in CKD are DNA methylation, histone acetylation, and histone methylation. These modifications regulate the transcription of genes involved in mitochondrial metabolism, oxidative stress responses, and inflammatory signaling pathways [21,22,117,118,119].

DNA methylation is catalyzed by DNA methyltransferases and typically occurs at cytosine residues within CpG islands. Hypermethylation of promoter regions can suppress gene expression, whereas hypomethylation may enhance transcriptional activity. In kidney disease, altered DNA methylation patterns have been identified in several genes involved in mitochondrial function, including mitochondrial processing peptidase subunit beta (PMPCB) and mitochondrial transcription factor A (TFAM). Dysregulation of these genes can impair mitochondrial protein processing, reduce mitochondrial DNA replication, and ultimately compromise mitochondrial respiration [21,22,96,120].

Histone modifications also play a critical role in regulating mitochondrial dynamics and oxidative stress responses. For example, increased acetylation of histone H3 lysine 27 (H3K27ac) has been associated with the activation of genes involved in mitochondrial fission and fibrosis in diabetic kidney disease. Similarly, phosphorylation of the mitochondrial fission protein Drp1 at serine 616 promotes mitochondrial fragmentation and has been linked to renal fibroblast activation and tubulointerstitial fibrosis [21,83,117,119].

Histone methyltransferases such as enhancer of zeste homolog 2 (EZH2) also contribute to mitochondrial dysfunction in CKD. EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) has been shown to repress antioxidant gene expression, thereby promoting oxidative stress and renal injury. Interestingly, mitochondrial metabolites such as S-adenosylmethionine (SAM) serve as methyl donors for histone methylation reactions, establishing a direct link between cellular metabolism and epigenetic regulation [22,117,118,119].

These findings highlight the existence of a metabolic–epigenetic feedback loop in which mitochondrial dysfunction alters cellular metabolism, which in turn modifies epigenetic landscapes that regulate mitochondrial gene expression. This cycle contributes to the persistence of oxidative stress and fibrosis in chronic kidney disease [21,22,117,118].

4.3. Non-Coding RNAs and Mitochondrial Regulation

Non-coding RNAs, particularly microRNAs (miRNAs), represent another important layer of regulation linking oxidative stress and mitochondrial dysfunction in kidney disease. MicroRNAs are short RNA molecules that regulate gene expression by binding to complementary sequences in target mRNAs, leading to translational repression or mRNA degradation [121,122,123].

Several microRNAs have been identified as regulators of mitochondrial dynamics and metabolism in renal cells. For instance, miR-668 has been shown to inhibit mitochondrial fission by targeting mitochondrial protein 18 (MTP18), thereby protecting renal tubular cells from apoptosis during ischemic injury. By suppressing excessive mitochondrial fragmentation, miR-668 helps preserve mitochondrial function and cellular viability [122,123].

Conversely, miR-17 has been implicated in the suppression of peroxisome proliferator-activated receptor alpha (PPAR-α), a transcription factor involved in fatty acid oxidation and mitochondrial metabolism. Downregulation of PPAR-α by miR-17 impairs mitochondrial energy metabolism and promotes cyst formation in polycystic kidney disease models [93,121,122,123].

These regulatory networks demonstrate how epigenetic and post-transcriptional mechanisms converge to influence mitochondrial function and oxidative stress responses. Understanding these pathways may provide new opportunities for therapeutic intervention aimed at restoring mitochondrial homeostasis in CKD [121,122,123,124,125].

5. Organelle Crosstalk: Mitochondria–Endoplasmic Reticulum Interactions

Mitochondria do not function as isolated organelles but instead participate in complex interactions with other cellular compartments. Among these interactions, communication between mitochondria and the endoplasmic reticulum (ER) plays a particularly important role in maintaining cellular homeostasis [76,80].

These interactions occur at specialized contact sites known as mitochondria-associated membranes (MAMs). MAMs facilitate the transfer of lipids, calcium ions, and metabolic intermediates between the ER and mitochondria, thereby coordinating cellular metabolism, calcium signaling, and stress responses [76,80,81].

In renal cells, MAMs are essential for regulating mitochondrial calcium uptake. Calcium ions released from the ER are transferred directly to mitochondria through channels such as the inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), and mitochondrial calcium uniporter (MCU). Controlled calcium transfer stimulates mitochondrial metabolism by activating dehydrogenases involved in the tricarboxylic acid (TCA) cycle [4,76,80].

However, excessive calcium transfer from the ER to mitochondria can lead to mitochondrial calcium overload, which disrupts mitochondrial membrane potential and triggers opening of the mitochondrial permeability transition pore (mPTP). This event results in mitochondrial swelling, release of pro-apoptotic factors, and activation of cell death pathways [31,76,126].

Disruption of MAM signaling has been implicated in various forms of kidney disease. Oxidative stress and mitochondrial dysfunction can alter ER–mitochondria communication, leading to abnormal calcium signaling and increased susceptibility to apoptosis [31,76,126].

Another important consequence of mitochondrial dysfunction is the release of mitochondrial DNA into the cytoplasm. Because mtDNA resembles bacterial DNA in structure, it can be recognized by innate immune receptors as a danger signal. One of the most important pathways activated by cytosolic mtDNA is the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway [17,126,127,128,129].

Activation of cGAS by mtDNA leads to the production of cyclic GMP–AMP (cGAMP), which activates STING on the ER membrane. STING signaling subsequently induces the production of type I interferons and pro-inflammatory cytokines, promoting inflammatory responses within the kidney [17,127].

Persistent activation of the cGAS–STING pathway has been implicated in chronic kidney disease and renal fibrosis. In experimental models, inhibition of STING signaling reduces inflammation and attenuates kidney injury, highlighting the importance of mitochondrial–immune crosstalk in renal pathology [17,127].

6. Disease-Specific Redox Mechanisms

Although oxidative stress and mitochondrial dysfunction represent common pathogenic mechanisms across different kidney diseases, the molecular pathways involved vary according to the underlying etiology, the dominant injured renal compartment, and the nature of the initiating insult [11,31]. In some settings, redox imbalance arises primarily from metabolic overload and mitochondrial substrate excess; in others, it is driven by podocyte injury, complement activation, chronic inflammation, or genetically determined alterations in calcium handling and cellular bioenergetics. Consequently, oxidative stress should not be regarded as a uniform downstream event, but rather as a disease-modifying process that acquires distinct molecular features in different nephropathies.

6.1. Diabetic Kidney Disease (DKD)

Diabetic kidney disease is the leading cause of chronic kidney disease worldwide and accounts for a substantial proportion of end-stage renal disease cases [12,130,131,132]. In this setting, hyperglycemia promotes a persistent state of metabolic oversupply that enhances mitochondrial electron flux, increases superoxide production, and favors oxidative injury to mitochondrial DNA, respiratory proteins, and membrane lipids [12,49,50,51,53,130,133,134,135,136,137]. However, the redox phenotype of DKD cannot be explained by mitochondrial ROS generation alone. Advanced glycation, lipotoxic stress, intrarenal RAAS activation, and inflammatory cytokines converge on ROS-generating systems, particularly NOX4, thereby amplifying oxidative injury and linking metabolic stress to structural renal damage.

In diabetic kidneys, excessive glucose exposure suppresses the activity of AMP-activated protein kinase (AMPK), a key metabolic sensor that normally supports mitochondrial biogenesis, fatty acid oxidation, and antioxidant defense [12,49,53,54,133,135,136,137]. Reduced AMPK signaling favors NOX4 upregulation and thereby intensifies ROS production in podocytes and tubular cells [12,48,53,54,55]. This interaction is mechanistically relevant because NOX4-derived oxidant signaling contributes not only to cellular injury but also to activation of profibrotic pathways, including transforming growth factor-β signaling, extracellular matrix deposition, and albuminuria progression. Experimental observations indicating that metformin restores AMPK activity and attenuates oxidative stress further support the view that mitochondrial dysfunction in DKD reflects defective adaptation to metabolic overload rather than a passive consequence of hyperglycemia alone [12,48,53,54,55].

Another important feature of DKD is the close integration between redox balance and mitochondrial quality control. Hyperglycemia suppresses the Sirt1–FOXO1 signaling axis, which normally promotes antioxidant gene expression, autophagy, and resistance to apoptosis [12,98,99,134,135]. Loss of this protective pathway renders renal cells more vulnerable to oxidative injury, especially in podocytes and proximal tubular epithelial cells, where sustained mitochondrial stress rapidly translates into cytoskeletal instability, slit diaphragm dysfunction, and fibrogenic signaling. Thus, the disease-specific redox signature of DKD is best understood as the combined result of mitochondrial ROS overproduction, impaired AMPK-dependent metabolic adaptation, NOX4 amplification, and defective Sirt1-mediated stress resistance.

6.2. Focal Segmental Glomerulosclerosis (FSGS)

Focal segmental glomerulosclerosis is characterized by progressive podocyte injury and segmental glomerular scarring [138,139]. Because podocytes are highly specialized cells with limited regenerative capacity and substantial bioenergetic requirements, mitochondrial dysfunction has particularly severe structural consequences in this disease. ATP depletion, excessive ROS generation, and impaired mitochondrial dynamics destabilize the actin cytoskeleton, promote detachment from the glomerular basement membrane, and accelerate podocyte loss, a central event in the transition from reversible glomerular stress to irreversible sclerosis [138,139].

The oxidative phenotype of FSGS is shaped by both mitochondrial and non-mitochondrial ROS sources. In addition to mitochondrial dysfunction, high NOX activity contributes to increased oxidant burden, inflammation, and fibrosis [140,141]. Persistent mtROS accumulation can damage lipids, proteins, and nucleic acids, thereby worsening mitochondrial bioenergetics and reinforcing podocyte vulnerability [142,143]. This process is clinically relevant because podocyte depletion is strongly associated with lesion progression, and once a critical threshold of podocyte loss is reached, segmental sclerosis becomes self-propagating.

Several signaling pathways connect redox stress to disease progression in FSGS. Nrf2-dependent antioxidant defense appears to have a protective role, and compounds such as citral, antroquinonol, and THSG have been shown experimentally to attenuate oxidative stress and glomerular injury through activation of the Nrf2/Keap1 pathway [138,139,144]. By contrast, HIF-1α-dependent signaling may aggravate damage under conditions of glomerular stress and hypoxia. Increased expression of angiopoietin-like protein 4 (ANGPTL4), a downstream target of HIF-1α, has been linked to oxidative stress and podocyte apoptosis, whereas epigallocatechin-3-gallate attenuates these changes through inhibition of the HIF-1α–ANGPTL4 axis [138,139,144,145]. In addition, microRNA-mediated pathways may intensify both oxidative injury and fibrosis, as illustrated by the HIF-1/miR-155-5p/Nrf2 axis, which has been implicated in inflammatory damage and progression of glomerular scarring [145]. Altogether, FSGS represents a disease in which oxidative stress is tightly linked to the structural fragility of the podocyte and to the progression from focal injury to permanent glomerular remodeling.

6.3. Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease is a genetic disorder caused by mutations in PKD1 or PKD2, resulting in altered calcium signaling, cyst formation, and progressive kidney enlargement [146]. In contrast to DKD and FSGS, oxidative stress in ADPKD is integrated with cystic metabolism, epithelial proliferation, and chloride-dependent fluid secretion. Mitochondrial dysfunction develops early in cystic tissue and contributes to reduced oxidative phosphorylation, altered ATP handling, and abnormal redox signaling that favor cyst expansion rather than simply reflecting advanced structural injury [146,147,148].

Experimental studies have shown that oxidative stress can precede overt cyst enlargement and may actively support disease progression. Nrf2 appears to be particularly relevant in this context. Reduced antioxidant defense promotes ROS accumulation and lipid peroxidation, whereas pharmacologic activation of Nrf2 attenuates oxidative damage and slows cyst growth in experimental models [28,29,66,67,68,148,149]. These findings are consistent with observations that compounds such as obacunone can limit lipid peroxide accumulation through the Nrf2/GPX4 axis and thereby restrain cyst progression [149,150].

The relationship between redox stress and epithelial fluid secretion is also central in ADPKD. Abnormal activation of chloride channels drives cyst fluid accumulation, and CFTR has long been considered a major mediator of this process [151]. AMPK activation has emerged as a potentially protective mechanism because it can suppress cell growth pathways and inhibit chloride-dependent secretion [152,153,154,155]. Agents such as metformin, PF-06409577, and steviol have been shown experimentally to activate AMPK, inhibit mTOR signaling, and reduce cystic expansion [151,152,153,154,155]. At the same time, recent work suggests that calcium-activated chloride conductances, including TMEM16A, may interact with or even dominate over CFTR in some cystic settings, indicating that the downstream secretory phenotype may be more heterogeneous than previously assumed. In this regard, ADPKD illustrates a distinctive redox-metabolic disease model in which oxidative stress is coupled to calcium dysregulation, proliferative reprogramming, and abnormal epithelial transport.

6.4. Membranous Nephropathy (MN)

Membranous nephropathy is an autoimmune glomerular disease and a major cause of adult nephrotic syndrome, characterized by subepithelial immune complex deposition and diffuse thickening of the glomerular basement membrane [156,157,158]. In this setting, oxidative stress is closely linked to complement-mediated podocyte injury rather than to metabolic substrate excess or primary mitochondrial disease. Immune complex deposition at the podocyte surface perturbs intracellular signaling, promotes inflammatory activation, and contributes to mitochondrial dysfunction, thereby amplifying structural damage to the filtration barrier. Experimental data increasingly support the concept that redox injury is an active component of the effector phase of MN rather than a nonspecific by-product of glomerular injury [159,160,161,162]. Recent primary evidence has further shown that complement stimulation can induce podocyte pyroptosis in MN and that mitochondrial dysfunction with ROS generation is a key component of this process.

The antioxidant response appears to be relevant in both experimental and potentially translational terms. Activation of the Nrf2/HO-1 pathway has been associated with attenuation of renal injury in experimental MN, and agents such as Sanqi oral solution, crocin, and curcumin have been shown to reduce oxidative stress and improve podocyte injury through Nrf2-centered pathways [159,160,161,162]. In parallel, autophagy-related mechanisms intersect with redox regulation. Salvianolic acid B and the combination of metformin with rapamycin have been reported to enhance autophagic responses and improve podocyte injury, supporting the view that mitochondrial quality control and oxidative stress are mechanistically linked in MN [163,164]. Ferroptotic mechanisms may also participate in disease progression. Passive Heymann nephritis studies have shown altered GPX4, GSH, and ACSL4 expression together with renal iron deposition, suggesting that ferritinophagy-associated ferroptosis may represent an additional oxidative injury pathway in MN [165,166,167,168]. Thus, in MN, oxidative stress appears to function as a bridge between immune complex/complement injury, mitochondrial dysfunction, and downstream podocyte loss.

6.5. Lupus Nephritis (LN)

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus and reflects the convergence of autoimmune inflammation, complement activation, immune cell infiltration, and intrinsic renal cell injury [169,170,171,172,173,174,175,176,177]. In contrast to DKD or ADPKD, the redox signature of LN is not confined to a single renal compartment but involves podocytes, mesangial cells, infiltrating leukocytes, and the systemic inflammatory milieu. Oxidative stress is increased in active disease and correlates with inflammatory burden and renal injury severity [175,176]. In this setting, mitochondrial dysfunction appears to be both a consequence of inflammatory injury and an amplifier of tissue damage through ROS generation, mitochondrial fragmentation, and inflammasome activation.

Recent evidence indicates that altered mitochondrial dynamics may be particularly important in podocyte injury in LN. Kidney biopsy-based studies have described abnormal mitochondrial morphology and increased expression of fission-related proteins such as Drp1 and Fis1 in podocytes, supporting a role for excessive mitochondrial fission in proteinuria and glomerular damage [174]. More recent primary work has shown that the C5a–C5aR1 axis can promote Drp1-mediated mitochondrial fission in podocytes, thereby linking complement activation directly to mitochondrial injury and structural glomerular damage in LN.

Several antioxidant and redox-regulating pathways have been implicated in disease modulation. Nrf2 suppresses lupus nephritis by limiting oxidative injury and restraining NF-κB- and TGF-β-related inflammatory signaling [177]. Citral and EGCG have both been shown experimentally to reduce oxidative stress and inflammatory activation through Nrf2-associated mechanisms [178,179]. Sirt1 has also emerged as a relevant protective factor because it can inhibit ROS-dependent activation of TRPM2-mediated Ca2+ influx and thereby limit NLRP3 inflammasome activity [169]. This is mechanistically important because ROS accumulation, calcium dysregulation, and inflammasome activation form a mutually reinforcing loop in active LN [169,171,172,173]. Clinical observations with N-acetylcysteine, although limited, also support the biological relevance of redox-targeted strategies in selected patients [170,180]. Overall, LN represents a disease in which mitochondrial dysfunction acts as an intermediary between immune activation and tissue injury, making oxidative stress central to both disease amplification and therapeutic vulnerability.

7. Clinical Evaluation: Redox and Mitochondrial Biomarkers in CKD

Traditional clinical markers used to monitor kidney disease—such as serum creatinine, estimated glomerular filtration rate (eGFR), and albuminuria—reflect functional decline rather than the underlying molecular mechanisms driving renal injury. Consequently, there is growing interest in identifying biomarkers capable of detecting oxidative stress and mitochondrial dysfunction at earlier stages of disease progression [24,71,181].

Oxidative stress biomarkers can be broadly classified into three categories: markers of lipid peroxidation, DNA oxidation, and protein oxidation. In addition, emerging biomarkers reflecting mitochondrial damage have attracted significant attention as potential tools for precision nephrology (Table 1) [24,71,181,182].

7.1. Lipid Peroxidation Markers

Lipid peroxidation is a hallmark of oxidative stress and occurs when reactive oxygen species attack polyunsaturated fatty acids within cellular membranes. Among the most reliable biomarkers of lipid peroxidation are F2-isoprostanes, which are prostaglandin-like compounds generated through free radical–mediated oxidation of arachidonic acid [183,184].

F2-isoprostanes are widely considered the gold standard for assessing in vivo oxidative stress due to their chemical stability and specificity. Elevated levels of F2-isoprostanes have been detected in plasma and urine samples from patients with chronic kidney disease and are associated with increased cardiovascular risk and accelerated renal decline [2,24,71,181,183,184].

The major urinary metabolite, 15-F₂t-isoprostane (15F₂tIsoPM), reflects systemic oxidative stress and provides a non-invasive indicator of lipid peroxidation. Accurate quantification of F2-isoprostanes typically requires mass spectrometry–based methods such as gas chromatography–mass spectrometry (GC–MS) or liquid chromatography–tandem mass spectrometry (LC–MS/MS). Although enzyme-linked immunosorbent assays (ELISA) are more accessible, they often overestimate concentrations due to cross-reactivity with related compounds [183,184].

7.2. DNA Oxidation Markers

Oxidative damage to DNA represents another important consequence of redox imbalance in CKD. One of the most widely studied biomarkers of DNA oxidation is 8-hydroxy-2′-deoxyguanosine (8-OHdG), which results from ROS-induced modification of guanine residues within DNA.

Elevated levels of 8-OHdG have been detected in both urine and plasma of CKD patients and are associated with increased mortality and cardiovascular complications. Urinary 8-OHdG reflects systemic oxidative DNA damage and has been proposed as an independent predictor of renal disease progression [2].

However, interpretation of 8-OHdG measurements requires caution because levels may be influenced by factors such as smoking, inflammation, and metabolic disorders. Moreover, variability in assay methodologies has limited its widespread clinical adoption.

7.3. Protein Oxidation Markers

Advanced oxidation protein products (AOPPs) represent another class of oxidative stress biomarkers relevant to CKD. AOPPs are formed through oxidative modification of plasma proteins, particularly albumin, by chlorinated oxidants generated during inflammatory processes [56,64,65,181,185].

Elevated circulating levels of AOPPs have been reported in CKD patients and are associated with increased oxidative stress, endothelial dysfunction, and cardiovascular complications. AOPPs can also stimulate inflammatory responses by activating monocytes and macrophages, thereby contributing to the vicious cycle of oxidative stress and inflammation in CKD [56,71,181,185].

Importantly, AOPPs have been linked to accelerated decline in glomerular filtration rate and may serve as predictors of disease progression [24,71,181].

7.4. Mitochondrial Biomarkers

Beyond traditional oxidative stress markers, increasing attention has been directed toward biomarkers reflecting mitochondrial damage. Among these, circulating mitochondrial DNA (mtDNA) has emerged as a promising indicator of mitochondrial dysfunction [127,128,182].

Mitochondrial DNA can be released into the circulation during cellular stress, apoptosis, or necrosis. Because mtDNA resembles bacterial DNA in structure, its presence in extracellular fluids can activate innate immune receptors and promote inflammatory responses [17,127,128].

Clinical studies have demonstrated that elevated levels of circulating or urinary mtDNA correlate with renal injury and disease severity in both acute kidney injury and chronic kidney disease. In particular, increased mtDNA copy number and fragmentation have been observed in patients with early renal dysfunction, suggesting that mtDNA may serve as an early biomarker of mitochondrial damage [186].

Despite these promising findings, several challenges remain before mitochondrial biomarkers can be routinely implemented in clinical practice. These include variability in sample processing, lack of standardized reference ranges, and potential confounding effects of systemic diseases [127,128,182].

Nevertheless, integrating mitochondrial biomarkers with traditional clinical parameters may improve early detection and risk stratification in CKD (Table 1) [24,182]

8. Therapeutic Strategies Targeting Oxidative Stress and Mitochondrial Dysfunction

Given the central role of oxidative stress and mitochondrial dysfunction in CKD progression, therapeutic strategies aimed at restoring redox balance and mitochondrial homeostasis have attracted considerable attention. These approaches range from established nephroprotective drugs with pleiotropic metabolic effects to novel mitochondria-targeted therapies and emerging biotechnological interventions (Figure 4, Table 2) [8,12,23,187,188].

8.1. Current CKD Therapies Targeting Oxidative Stress and Mitochondrial Dysfunction

Several drugs currently used in CKD management exert beneficial effects on mitochondrial metabolism and oxidative stress pathways [8,12,23,187,188].

Among these, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as one of the most important therapeutic breakthroughs in nephrology. Originally developed as glucose-lowering agents for type 2 diabetes, SGLT2 inhibitors have demonstrated remarkable nephroprotective and cardioprotective effects in multiple large-scale clinical trials [189,190,191,192].

Beyond their metabolic effects, SGLT2 inhibitors improve mitochondrial function by activating nutrient-deprivation signaling pathways such as AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). Activation of these pathways suppresses the mammalian target of rapamycin (mTOR) signaling cascade, thereby promoting autophagy and mitochondrial quality control [12,53,54,55].

Renin–angiotensin–aldosterone system (RAAS) inhibitors—including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers—also exhibit antioxidant effects by reducing angiotensin II–mediated ROS production. By limiting activation of NADPH oxidases, these agents reduce oxidative stress and slow the progression of renal fibrosis [40,44,56,193].

8.2. Mitochondria-Targeted Antioxidants

Conventional antioxidants have generally shown limited success in clinical trials due to poor mitochondrial targeting. As a result, considerable effort has been directed toward developing antioxidants specifically designed to accumulate within mitochondria [8,23,187,188].

One of the most extensively studied compounds is MitoQ, a mitochondria-targeted derivative of coenzyme Q10 that selectively accumulates within the inner mitochondrial membrane. By neutralizing ROS at their primary site of production, MitoQ has demonstrated protective effects in experimental models of kidney injury [23,187,188,194].

Another promising compound is SS-31 (elamipretide), a mitochondria-targeted tetrapeptide that binds to cardiolipin, a phospholipid located in the inner mitochondrial membrane. By stabilizing cardiolipin and improving electron transport chain efficiency, SS-31 enhances mitochondrial respiration and reduces ROS generation [187,188,195,196].

Notably, elamipretide recently received regulatory approval for the treatment of Barth syndrome, providing proof-of-concept for the clinical viability of mitochondria-targeted therapies [186].

8.3. Activation of the Nrf2 Antioxidant Pathway

The Nrf2 signaling pathway represents one of the most important cellular defense mechanisms against oxidative stress. Activation of Nrf2 promotes the transcription of numerous antioxidant and cytoprotective genes, including heme oxygenase-1 (HO-1), glutathione synthesis enzymes, and detoxification proteins [28,29,66,67,68,116].

Bardoxolone methyl, a potent Nrf2 activator, has shown promising results in clinical trials involving patients with diabetic kidney disease. Early studies demonstrated significant improvements in estimated glomerular filtration rate following bardoxolone treatment [197,198,199].

However, the BEACON trial raised safety concerns due to increased rates of heart failure among treated patients. Subsequent trials with improved patient selection criteria have suggested that Nrf2 activation may still represent a viable therapeutic strategy in CKD [66,198,199,200,201].

8.4. Emerging Therapeutic Approaches

In addition to pharmacological interventions, several innovative strategies are being explored to restore mitochondrial function in kidney disease [187,188].

Mitochondrial transplantation represents a novel approach involving the delivery of functional mitochondria into injured tissues. Experimental studies have shown that transplantation of healthy mitochondria can restore cellular bioenergetics and reduce inflammation in models of kidney injury [187,188].

Nanotechnology-based drug delivery systems also offer promising opportunities for targeted therapy. Nanoparticles designed to accumulate in renal mitochondria can deliver antioxidants or therapeutic molecules directly to sites of oxidative damage while minimizing systemic side effects [187,188].

These approaches remain in early stages of development but illustrate the rapidly evolving landscape of mitochondrial medicine.

9. Lifestyle, Metabolism, and Hormonal Influences

Lifestyle factors and metabolic conditions play important roles in modulating oxidative stress and mitochondrial function in the kidney [202].

Obesity and metabolic syndrome are major risk factors for chronic kidney disease and are associated with increased mitochondrial oxidative stress. Experimental studies have demonstrated that high-fat diets induce a biphasic mitochondrial response in renal tissue. In early stages, compensatory increases in antioxidant defenses may temporarily maintain mitochondrial function. However, prolonged exposure to metabolic stress leads to mitochondrial dysfunction, reduced mitochondrial DNA copy number, and increased lipid peroxidation [55,186,203,204].

Hormonal factors also influence mitochondrial homeostasis. Estrogen has been shown to exert protective effects on mitochondrial function by enhancing antioxidant enzyme activity and regulating mitochondrial calcium handling. These effects may partly explain the lower incidence of CKD observed in premenopausal women [202].

Thyroid hormones represent another important regulator of mitochondrial metabolism. Hypothyroidism, which is common in advanced CKD, is associated with reduced mitochondrial respiration and impaired energy metabolism, potentially contributing to accelerated renal decline [202,205,206,207].

Dietary interventions aimed at improving mitochondrial metabolism—such as caloric restriction, ketogenic diets, and increased intake of antioxidant-rich foods—have been proposed as complementary strategies for slowing CKD progression. Although clinical evidence remains limited, these approaches highlight the importance of metabolic health in maintaining renal mitochondrial function [185,203,208].

10. Conclusions and Future Perspectives

Chronic kidney disease is increasingly recognized as a disorder driven by profound disturbances in mitochondrial metabolism and redox homeostasis. The kidney’s exceptional reliance on mitochondrial oxidative phosphorylation renders it particularly vulnerable to bioenergetic failure, making mitochondrial dysfunction a central driver of disease progression.

Disruption of mitochondrial quality control mechanisms—including impaired mitochondrial dynamics, defective mitophagy, and reduced mitochondrial biogenesis—leads to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species. These processes trigger inflammation, cellular apoptosis, and fibrosis, ultimately contributing to progressive loss of renal function.

Emerging pathogenic mechanisms such as ferroptosis, epigenetic regulation of mitochondrial genes, and mitochondrial DNA–mediated immune activation have further expanded our understanding of the complex interactions linking oxidative stress and kidney disease.

From a clinical perspective, the identification of reliable biomarkers reflecting oxidative stress and mitochondrial injury may enable earlier detection of disease and facilitate personalized therapeutic strategies. At the same time, the development of mitochondria-targeted therapies—including targeted antioxidants, mitophagy modulators, and mitochondrial transplantation—offers exciting opportunities for future interventions.

Ultimately, translating these mechanistic insights into effective therapies will require multidisciplinary collaboration integrating molecular biology, clinical nephrology, and systems medicine. By targeting the fundamental mechanisms of mitochondrial dysfunction, it may be possible to shift the paradigm of CKD treatment from symptomatic management toward mechanism-based precision medicine capable of improving long-term renal outcomes.