Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition

Jairo Lumpuy-Castillo; Isabel Amador-Martínez; Miriam Díaz-Rojas; Oscar Lorenzo; José Pedraza-Chaverri; Laura Gabriela Sánchez-Lozada; Omar Emiliano Aparicio-Trejo

doi:10.1016/j.redox.2024.103340

. 2024 Sep 5;76:103340. doi: 10.1016/j.redox.2024.103340

Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition

Jairo Lumpuy-Castillo ^a,¹, Isabel Amador-Martínez ^b,^c,¹, Miriam Díaz-Rojas ^d, Oscar Lorenzo ^a, José Pedraza-Chaverri ^c, Laura Gabriela Sánchez-Lozada ^b, Omar Emiliano Aparicio-Trejo ^b,^⁎

PMCID: PMC11407069 PMID: 39250857

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.

Keywords: Acute kidney injury, Chronic kidney disease, Cardio-renal syndromes, Mitochondrial dysfunction, Glutathione, Redox signaling, AMPK, SIRT1/3, PGC-1α

Graphical abstract

Highlights

•
Mitochondrial redox imbalances promotes AKI to CKD progression and CRS development.
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Metabolic reprograming and disrupted mitochondrial biogenesis enhances CRS type 3 and 4.
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NAC have shown promise CRS protection associated to AMPK-SIRT1/3-PGC-1α axis.

1. Introduction

The interaction between the heart and the kidney are vital for maintaining systemic homeostasis, but disruptions in this communication can lead to various forms of cardio-renal syndrome (CRS). The mechanisms underlying CRS involve hemodynamic, neurohormonal, and inflammatory factors. CRS was firstly defined and classified by the Acute Dialysis Quality Initiative (ADQI) in 2008 [1]. This classification became complex in clinical practice due to the difficulty in determining the origin and causal relationships, and the presence of shared risk factors, such as diabetes and hypertension [2]. In type-1 CRS, acute heart failure (HF; i.e., decompensated HF or acute myocardial infarction) leads to acute kidney injury (AKI), while in type-2 CRS, chronic HF (i.e., congestive HF) contributes to the development of chronic kidney disease (CKD). More important for this review is type-3 CRS, where AKI (i.e., acute interstitial nephritis, bilateral ureteral obstruction) induces acute HF. On the other hand, in type-4 CRS, a long-term CKD triggers the development or progression of chronic HF [3]. Thus, the reno-cardiac syndromes (types 3 and 4) are characterized by primary renal events, either AKI or CKD, preceding cardiac dysfunction [4].

AKI is characterized by the sudden loss of kidney function and is clinically determined by increased serum creatinine levels [5]. It is associated with a 38 % higher risk of major cardiovascular events (i.e., acute myocardial infarction) and with 86 % elevated cardiovascular mortality [6]. Also, AKI was linked to a more than 50 % increased risk of HF and arrhythmias [7]. The incidence of CRS type 3 has been described in 17–29 % [8,9]. In particular, AKI is present in 2–60 % of the population and can be influenced by various risk factors and clinical conditions [10,11]. In animal models, both HF and rhythm disturbances occurred shortly after AKI due to ischemia/reperfusion (I/R) [12,13]. Interestingly, changes in the metabolomics profile of the heart after AKI-I/R were related to metabolic reprogramming, as occurs after myocardial ischemia [14]. Remarkably, one-third of AKI cases do not fully recover, leading to persistent kidney dysfunction and an increased risk of developing CKD [15]. Indeed, Abdala et al. estimated an odd ratio of 4.31 (95 % CI 3.01–6.17; p < 0.01) for CKD development in AKI patients [16].

In CKD, an intricate bidirectional interaction with the cardiovascular system can damage the kidney and the heart. CKD and HF frequently co-occur, affecting approximately 50 % of patients with either condition [17]. CKD is defined as abnormalities of the structure or function of the kidney, which are maintained for at least three months. Its primary drivers include aging, diabetes, and hypertension [18]. The global prevalence of CKD has increased to 9.1 % [18], which may be responsible for the increased prevalence of type-4 CRS (5.5–76.25 %) [[19], [20], [21]]. End-stage renal disease (ESRD), the most severe form of CKD, is fatal without dialysis or kidney transplantation [22,23]. The pathophysiology of CKD is complex and involves dysregulated molecular mechanisms in the kidney that lead to maladaptive responses. CKD doubles the risk of patients developing HF and coronary heart disease [24]. Also, it triggers a higher risk of atrial fibrillation, ventricular arrhythmias, and sudden cardiac death [25]. CKD patients have a 10-20-fold increased risk of cardiac mortality compared to age- and gender-matched control subjects [26]. In this regard, HF is the leading cause of mortality in CKD patients, and 7.6 % of deaths from CVD were attributable to CKD [18,27].

Mitochondria are now considered vital cellular signaling and metabolism regulators, transcending their well-known function in energy production [28]. In 5/6 nephrectomy-induced CRS 4 models, mitochondrial damage and apoptosis play an essential role in developing cardiac dysfunction [29,30]. Additionally, mitochondria are considered one of the main sites of reactive oxygen species (ROS) production and redox signaling regulation. Mitochondria contain their own distinct pool of glutathione reduced/glutathione disulfide (GSH/GSSG), which maintains the organelle's redox balance and plays a crucial role in regulating key energy metabolic pathways [31]. Several proteins and factors, including those from mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), β-oxidation, Krebs cycle, redox signaling, and sirtuins (SIRT), are sensitive to GSH/GSSG changes leading to mitochondrial alterations [32]. Notably, the disruption of mitochondrial GSH/GSSG homeostasis has been identified as a critical feature of CKD, making interventions that normalize this balance a potential therapeutic target [33].

This review explores the pathophysiological molecular mechanisms underlying metabolic reprogramming in AKI, CKD, and the associated type 3 and 4 CRS, with a focus on glutathione redox signaling and the AMP-activated protein kinase (AMPK) -SIRT1/3- peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis.

On the other hand, N-acetylcysteine (NAC), a thiol-containing antioxidant known to replenish intracellular GSH [34], has shown promise in addressing oxidative stress and mitochondrial dysfunction in renal, cardiac, and cardio-renal diseases [34,35]. We will delve into the current understanding of NAC's role in modulating cellular and mitochondrial GSH/GSSG status, particularly its interaction with SIRT1 and SIRT3, in the context of CKD and CRS. This comprehensive analysis aims to shed light on the potential of NAC as a therapeutic strategy for mitigating oxidative stress, restoring mitochondrial function, and potentially improving outcomes in these complex disease states.

2. Mitochondrial bioenergetics impairment and metabolic reprogramming from AKI to CKD and reno-cardiac diseases

The kidney is the second energy-consuming organ, behind the heart and ahead of the brain, with an estimated metabolic rate of >400 kcal/kg tissue/day [36], mainly used for reabsorption of ions and glucose production. Thus, renal oxygen consumption (VO₂) ≈ of 10 ml/min represents two-thirds of the cardiac VO₂ and requires approximately 20 % of cardiac output [37,38]. More than 80 % of the renal O₂ consumption is attributable to the active transport mechanisms derived from Na⁺/K⁺-ATPase activity. Therefore, mitochondrial density through the tubular nephron segments is highly enriched [39]. Fig. 1 illustrates the segment-specific energy production profile in the kidney, with OXPHOS dominating ATP generation in the outer cortex and glycolysis becoming increasingly important in the inner medulla under hypoxic conditions (PO₂ 10–15 mmHg) [37,38].

Fig. 1 — **Energetic Metabolism Across Nephron Segments and them correspond alteration in AKI and CKD transitions.** The figure depicts the variation in energy production pathways along different segments of the nephron. In the renal cortex, characterized by higher oxygen partial pressure (PO2), the proximal tubule (PT), cortical thick ascending limb (CATL), and distal convoluted tubule (DCT) demonstrate higher mitochondrial density and a greater reliance on oxidative phosphorylation (OXPHOS) for ATP production. Conversely, the inner medullary tubular segments predominantly utilize glycolysis, supplemented by metabolites from the proximal tubule. AKI= Acute kidney disease: ATL = ascending thin limb of Henle's loop; CATL = cortical thick ascending limb; CKD = cronic kidney disease; DCT = distal convoluted tubule OXPHOS = oxidative phosphorylation; PO₂ = oxygen partial pressure; PT = proximal tubule; ROS = reactive oxygen spices; TDL = thin descending limb of Henle's loops; ΔΨm = mitochondrial membrane potential. Created with *BioRender*.

The proximal convoluted tubule (PCT) exhibits a distinct metabolic specialization, relying exclusively on mitochondrial oxidation of preferred substrates (fatty acids, lactic acid, citrate, and glutamate) for energy generation, as it lacks the enzymes necessary for glycolysis (Fig. 1) [39,40]. This agrees with the higher susceptibility of PCT cells to experience mitochondrial membrane potential (ΔΨm) depolarization in pathological situations, which is linked to the ATP synthase's inability to hydrolyze ATP via reverse activity [41,42]. Mitochondrial β-oxidation in the PCT supports both reabsorption and gluconeogenesis. The glucose produced via gluconeogenesis is essential for the metabolically active cells in the medulla. Additionally, lactate generated in the medulla is transported to the PCT and utilized as a substrate in the gluconeogenesis, establishing a metabolic cycle [43]. Therefore, energetic homeostasis in PCT is fundamental for maintaining the medullar nephron segment bioenergetics.

In the heart, one-third of cardiomyocyte volume is occupied by mitochondria, providing up to 95 % of the required ATP, mainly from β-oxidation [44,45]. Interestingly, mitochondrial dysfunction observed in the kidneys during AKI and CKD appears to be mirrored in the heart during CRS, [2,34,46,47]. This suggests a shared pathophysiological mechanism, resulting in cardiac metabolic reprogramming, diminished ATP production from β-oxidation and increasing ROS generation [34,46]. Despite their potential significance for developing novel therapeutic strategies, the precise pathophysiological mechanisms linking mitochondrial impairment to type-3 and -4 CRS remain poorly elucidated [2,46].

In this section, we highlight the early deterioration of mitochondrial components, specifically the electron transport system (ETS) and β-oxidation, alongside the reduction of gluconeogenesis and the increase of glycolytic pathways in the kidney. These alterations are common mechanisms underlying the progression of AKI and CKD. Additionally, we present recent evidence demonstrating a similar metabolic reprogramming in the heart in CRS types 3 and 4.

2.1. Lipid accumulation and reduction of the fatty-acid β-oxidation in reno-cardiac disease

The accumulation of lipids in the kidney and plasma represents a prominent and potentially critical early event in the pathogenesis of CKD, as evidenced by multiple experimental models [[48], [49], [50]]. An early increase in triglyceride synthesis and release of fatty acids persists into the more advanced stages of renal injury [51,52]. Moreover, dyslipidemia affects approximately one-third of patients in the early stages of renal dysfunction [53], with plasma levels of triglycerides, cholesterol, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL) increasing as CKD progresses [48,54]. Within the nephron, the proximal tubule and glomerulus are particularly vulnerable to lipid accumulation, which can contribute to the initiation and progression of renal damage [48,55,56]. This vulnerability has been linked with the rise of the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) and the lipid uptake transporters, cluster of differentiation 36 (CD36), and the fatty acid binding protein (FABP) [48,57,58]. Also, key lipogenesis factors, such as the sterol regulatory element-binding protein1 (SREBP1), are overexpressed in patients with CKD [59]. In parallel, the deregulation of CCAAT/enhancer binding protein-α (C/EBP-α), a transcription factor that interacts with PPAR-γ in lipogenesis, promotes lipid accumulation and renal fibrosis [60]. Notably, renal fatty acid accumulation activates macrophage infiltration and pro-fibrotic pathways (i.e., TGF-β) [61,62]. Indeed, overexpression of CD36 in mice induced metabolic reprogramming characterized by enhanced fatty acid β-oxidation and epithelial-mesenchymal transition, ultimately promoting the development of CKD [55].

Intriguingly, renal lipid accumulation has been attributed to reduced β-oxidation, ETS, and OXPHOS [55,61,63,64]. In experimental models of renal mass reduction, obstruction, and cytotoxicity, the decreased activity and expression of β-oxidation enzymes precede the overproduction of reactive oxygen species (ROS) and subsequent pro-inflammatory and profibrotic processes [55,61,63,64]. This downregulation of β-oxidation enzymes predominantly affects the proximal tubular and glomerular segments [49,61,65], correlating with an early decline in complex I (CI) activity and mitochondrial uncoupling, further increasing ROS production [61,63,64]. Additionally, this decreased β-oxidation has been linked impaired mitochondrial biogenesis, mediated by the PGC-1α/AMPK signaling pathway in animal models [63,64,66] and patients [67]. This response perpetuates lipid accumulation and further diminishes mitochondrial β-oxidation, establishing a vicious circle that favors metabolic reprogramming.

Likewise, heart function depends primarily on mitochondria β-oxidation [68]. In cases where the demand for ATP is high, glycolysis enhancers can compensate the β-oxidation However, the lack of flexibility between these energy sources leads to reduced cardiac efficiency and impaired contractility [69]. CKD can induce functional and structural cardiac abnormalities, characteristic of heart failure [21]. In heart failure, the heart modifies its energy substrate utilization as a compensatory mechanism, which ultimately culminates in pathological cardiac remodeling [70]. Interestingly, a recently published study observed that the development of type 4 CRS in a UUO model was markedly characterized by the downregulation of genes related to oxidative mitochondrial β-oxidation [71]. Another study showed that CKD promotes high phosphate concentrations in myocardial mitochondria and decreases OXPHOS and FA metabolism. These effects were attributed to the downregulation of PGC-1α in an interferon regulatory factor 1 (IRF1)-dependent manner [72]. Notably, there is a paucity of research investigating the specific molecular alterations driving cardiac pathology during fatty-acid β-oxidation in the context of type 3 and 4 CRS. A deeper understanding of this metabolic pathway in these conditions is crucial for developing targeted therapeutic interventions.

2.2. Alterations of the Krebs cycle and OXPHOS

The loss of functional nephrons during CKD induces higher solute reabsorption and hemodynamic changes in the remaining nephrons. This promotes increased metabolic rates and ATP consumption in the tubular segments [61,73]. Likewise, oxidative stress and inflammation decrease O₂ supply and induce mitochondrial decoupling [61,64,74], reducing ATP production [75,76]. Consequently, mitochondria in the renal cortex cannot meet the increased ATP demand [61,64,77]. Due to alterations in the Krebs cycle and ETS, primarily in the proximal tubule, ATP levels decrease by 25 %–70 % in AKI and CKD, respectively [61,64,77].

The Krebs cycle intermediates are strongly affected in AKI and CKD, as evidenced by the alteration of related enzymes and metabolites [[78], [79], [80]] (Fig. 2A). Dynamic regulation, release and excretion of these factors may depend on kidney damage injury. Citrate accumulation is observed in obstructive and ischemic models in parallel to a decline in renal aconitase activity [61,79,[81], [82], [83]]. Increased urinary excretion of α-ketoglutarate (α-KG) is consistent with the reduction in renal isocitrate dehydrogenase-3 in CKD patients, which results in lower concentration of α-KG in blood serum [79,84,85]. Similarly, alterations in succinyl-CoA or succinate dehydrogenase (SDH, also named mitochondrial complex II, CII) were associated with decreased levels of urine and renal succinate in CKD patients [86]. However, as a compensatory mechanism, succinate can be stimulated by increased activity of SDH [81,82,87]. Thus, succinate metabolism is a significant area of research in the context of CRS.

Fig. 2 — **Metabolic Reprogramming in Kidney and Heart Disease. A)** AKI to CKD Transition. Mitochondrial dysfunction, evident from early AKI to CKD progression, is characterized by decreased TCA cycle, β-oxidation, and ETS activity. This leads to a drop in mitochondrial membrane potential (ΔΨm), ATP production, and increased reactive oxygen species (ROS) generation. Consequently, gluconeogenesis, anaplerotic reactions, and glutamate release by the proximal tubule are inhibited. β-oxidation inhibition increases lipogenesis factors and intracellular lipid accumulation. Elevated mitochondrial ROS favors damage-associated molecular patterns (DAMPs) accumulation and angiotensin II (Ang II) activation, enhancing the hypoxia-inducible factor 1-alpha (HIF-1α) pathway and inhibiting peroxisome proliferator-activated receptor alpha (PPARα)/Forkhead box O1 (FOXO1). This increases glycolysis and extracellular vesicle (EV) secretion, contributing to metabolic reprogramming in distal segments through EV action on receptor cells. B) Cardiomyocytes Reprogramming in Cardiorenal Syndrome (CRS). In CRS types 3 and 4, pathological processes stemming from renal impairment (pressure overload, oxidative stress, increased cardio-renal connectors) induce HIF-1α pathway activation in the heart. This, coupled with reduced mitochondrial biogenesis and Krebs cycle regulators (e.g., pyruvate kinase M1 [PKM1]), leads to decreased ETS activity and mitochondrial OXPHOS. Reduced OXPHOS increases glycolytic pathways (e.g., estrogen-related receptor gamma [ERRγ] and Hippo/Yes-associated protein 1 [YAP1]), enhancing glucose utilization.

ACO: aconitase; Ang II: angiotensin II pathway, ANT: adenine nucleotide translocator; αKDH: alpha-ketoglutarate dehydrogenase; CI: complex I, CIII: complex III; CIV: complex IV; CD36: cluster of differentiation 36; CPT1: Carnitine palmitoyl transferase; DAMPs: damage-associated molecular patterns; EVs: extracellular vesicles; FABP1: fatty acid-binding protein 1; FOXO1: forkhead box protein O1; Glu: glucose; GLUT 1 = glucose transporter 1,I DH: isocitrate dehydrogenase; MDH: malate dehydrogenase; NF-κB: nuclear factor kappa B; PKM1 = pyruvate kinase muscle isozyme 1, PPAR-α/γ: peroxisome proliferator-activated receptor alpha/gamma; ROS: reactive oxygen spices; SREBP1: sterol regulatory element binding protein 1; TCA: tricarboxylic acid cycle; TGF-β: transforming growth factor-beta; V/LDL = very/low-density lipoprotein; YAP1= Yes-associated protein 1; ΔΨm = mitochondrial membrane potential. *Figure created usingBioRender.com*.

Accumulation of succinate in kidney could induce its release to the circulation [88]. There is no solid evidence related to alterations of succinate in serum from AKI patients, but after experimental I/R-induced AKI, succinate was also increased in kidney and plasma [82,87]. In the proximal tubule, succinate alters respiration and stimulates membrane hyperpolarization by increasing K⁺ uptake [89,90]. It also promotes arachidonic acid, prostaglandin -E2 and -I2 discharge, which favors renin release [90,91]. Succinate inhibits 2-oxoglutarate dehydrogenase (2OGDH) and stabilize the hypoxia-inducible factor-1 α (HIF-1α) [92]. HIF-1α improves eGFR but acts as a pro-inflammatory signal promoting the expression of IL-1β in macrophages [92]. Therefore, succinate participates in the inflammatory response of kidney diseases. In fact, plasma succinate correlated negatively with eGFR in CKD patients [93]. In this context, succinate may play a multifaceted role in managing HF. Targeting metabolism of the mitochondrial succinate has emerged as a promising strategy to prevent I/R injury. Malonate, a competitive inhibitor of SDH, can reduce infarct size in models of acute myocardial infarction by this preventing ROS production by at mitochondrial complex I [93]. Also, reducing SDH partially reversed metabolic reprogramming and promoted adult cardiomyocyte regeneration [93]. However, succinate may exacerbate mitochondrial dysfunction by enhancing mitochondrial fission and cardiomyocyte apoptosis. Succinate accumulation was also linked to cardiac hypertrophy [94], and may trigger metabolic remodeling and epigenetic changes that alter myocardial gene expression toward imbalanced FAO/glycolysis [95]. The interplay between CKD, HF, and succinate metabolism warrants further exploration. In general, reduction in the Krebs cycle activity has been attributable to oxidative stress and downregulation of mitochondrial regulators [[78], [79], [80]].

Additionally, a reduction in mitochondrial ETS activity appears to be a common pathological mechanism in animals and patients with CKD [55,66,67]. The CI activity decreased as early as the first day in animal models of renal mass reduction or cytotoxicity [35,96,97]. Obstructive models exhibited a similar decrease in CI activity but at later time points [63,83]. As is shown in Fig. 2 A, the increased susceptibility of CI to renal injury is closely linked to the rapid development of oxidative stress [35,65,96,98] and the irreversible oxidation of redox-susceptible free cysteines at this complex [99]. Additionally, the activities of complex III (CIII) and complex IV (CIV) decreased throughout the first month of injury [35,83,96,97]. CII activity is also diminished in models of ischemia, renal obstruction, and nephrectomy [65,83,100,101]. However, a slight increase in CII-linked respiration was detected in early stages of nephrectomy and age-related models [102,103], suggesting a compensatory mechanism for the drastic decrease of CI [65,102]. Finally, ATP synthase activity is also reduced in AKI and in CKD [35,96,97]. This response reduces mitochondrial ATP production, particularly in cortical segments, due to mitochondrial uncoupling and lower mitochondrial mass [35,63,64,96].

Oxidative stress in the heart is produced during AKI. Thus, the association of oxidative stress and mitochondrial disturbances closely produces cardiac pathology. In this sense, it has been demonstrated that OXPHOS and membrane potential are initially affected by disturbances in CI activity and GSH depletion [104]. Other stressors in AKI, such as hemodynamic impairment may also trigger endoplasmic reticulum stress activating metabolic reprogramming and both protective and detrimental pathways like X-box binding protein 1 and the inositol-requiring enzyme 1α [105].

Most of the heart's ATP is produced through OXPHOS in the mitochondria. However, during HF or cardiac remodeling, OXPHOS is significantly affected by mitochondrial impairment [70]. HF is a common complication of CKD, often induced by pressure overload [21]. In HF, metabolic modifications can occur, affecting the oxidative capacity of mitochondria in an estrogen-related receptor γ (ERRγ) dependent manner. In adenine-induced CKD, the capacity of OXPHOS in cardiac muscle was reduced by 30 %. These alterations were associated with the oxidation of the redox potential and a modest decrease of ΔΨm, potentially explained by the reduced activity of the alpha-ketoglutarate dehydrogenase (αKGDH) and CIV [106]. Few studies have investigated cardiac mitochondria in CRS type III and IV. However, CKD has been shown to impair skeletal muscle mitochondrial function, as evidenced by decreased respiratory control index and increased hydrogen peroxide (H₂O₂) production [107]. Our group reported a similar decrease in the respiratory control index in CI and CII-linked respiration in cardiac mitochondria in 5/6 nephrectomy-induced CRS type IV [108]. Similarly, folic acid-induced CRS type III is also associated with decreased CI and CII activity, reducing cardiac mitochondria ATP production [34]. As shown in Fig. 2B, early alteration in the cardiac OXPHOS system has been linked to the promotion of CRS type III and IV. It is important to note that further research is needed to fully understand the cardiac profile and its association with alterations in OXPHOS in the pathological pathways that trigger CRS development.

2.3. Modification of glycolysis and gluconeogenesis

Under normal conditions, glycolytic ATP production is predominant in endothelial cells from distal segments and mesangial cells, but not in S1 and S2 proximal tubules [39,109]. In the renal cortex, PO₂ and OXPHOS are higher than in the deeper medulla, where PO₂ is low, and glycolysis is the main source of ATP [39,110,111]. However, cells in the thick ascending limb of Henle and other distal tubule segments can switch from OXPHOS to glycolysis when faced with PO₂ reduction, making them less sensitive to hypoxia [109,112,113]. After renal injury, the reduction of β-oxidation in the proximal tubule is accompanied by glycolysis activation [62], which may be an early adaptation to maintain energy balance and tissue regeneration. However, it's important to note that enhanced glycolysis, while initially beneficial, is insufficient to maintain ATP levels over time, and its prevalence can promote pro-inflammatory and -fibrotic responses [56,114,115]. Moreover, glycolytic metabolism increases renal fibroblast proliferation and the production of TGF-β, fibronectin, and alpha-smooth muscle actin (α-SMA) [116,117]. In fact, renal biopsies from CKD patients have shown an increase in glycolytic enzymes and inflammation markers [115]. In experimental AKI and CKD, inhibiting glycolytic enzymes or glucose transporters reduced renal lactate and acid uric levels, along with apoptosis, inflammation, and fibrosis [[118], [119], [120]].

Furthermore, the increase of glycolytic pathways has also been related to the activation of the HIF-1α [121]. Early renal hypoxia is induced by hemodynamic changes, including increased renal resistance, damage to blood vessels, decreased nitric oxide (NO), and increased oxygen consumption by immune and proximal tubule cells [36,121,122]. Renal hypoxia then induces prolyl hydroxylase inactivation and HIF-1α stabilization. Additionally, the pro-oxidative environment favors HIF-1α production through NF-kB- and angiotensin II/PI3K/PKC-dependent mechanisms [[123], [124], [125]]. In turn, HIF-1α increases glucose flux by upregulating the expression of glycolytic enzymes and transporters. Conversely, HIF-1α decreases ETS activity, mitochondrial biogenesis and induces mitochondrial degradation [121,126]. Interestingly, in CKD, HIF-1α also stimulates the production of extracellular vesicles (EVs) from renal cells, which are exported to distal cells potentially for metabolic reprogramming [98,127,128]. The content of these EVs can be modified by hypoxia, enriching their cargo with glycolytic enzymes and microRNAs (miRNAs) [129,130]. This response has also been implicated in diabetic nephropathy (DN) development under high glucose conditions [131]. Similarly, in ischemia/reperfusion and obstructive-induced CKD, the HIF-1α-stimulated EVs from tubular epithelial cells stimulate metabolic reprogramming and the production of inflammatory cytokines production in renal macrophages and distal tubule cells [132,133]. Thus, HIF-1α may extend metabolic reprogramming from proximal to distal segments.

In addition, renal gluconeogenesis takes place exclusively in the proximal tubule, where lactate, glutamine and glycerol are used as substrates instead of hexoses or other carbohydrates [[134], [135], [136]]. Lactate is responsible for half of glucose production and is principally taken up at the apical membrane of S2 and S3 segments by monocarboxylate transporters 1 and 2 [137,138]. Despite this, glucose production in the kidney is the second highest (after the liver) with a renal net balance of 1 mmol/kg/min [43,136]. However, the kidney is both a glucose producer (in the cortex) and a consumer (in the medulla). The distal tubule, thick ascending limb of Henle, convoluted tubules, and collecting ducts can receive glucose from the proximal tubule. These segments produce lactate, which returns to the cortex to enter into the gluconeogenic pathway, establishing a cortical-medullary recycling loop [43,136,139]. Furthermore, gluconeogenesis is important for anaplerotic reactions that restore Krebs cycle intermediates and, thereby, subsequent mitochondrial function [40,138,140]. In this regard, changes in gluconeogenesis have been observed in patients with AKI and during the progression to CKD. Renal biopsies have unveiled reduced levels of gluconeogenic enzymes alongside disruptions in glucose production and lactate clearance in the proximal tubules from the early stages of injury. In proteinuria-, ischemic-, and obstructive-CKD models, the downregulation of PPARα, HNF4a and FOXO1 decreased gluconeogenic enzymes in the proximal tubule, which was related to an increase in TGF-β and kidney fibrosis, thereby increasing the mortality rate [141,142]. These responses were associated with a lowering of PGC1-α and an increase in HIF-1α in both AKI and CKD models [56,[78], [79], [80],114,115,121]. Thus, the switches in metabolic reprogramming induce a direct reduction in gluconeogenesis and an indirectly reduction by lowering the ATP production by OXPHOS.

In physiological conditions, the heart relies minimally on glucose for energy metabolism [143]. However, in pathological conditions, the increase in energy demands is met by enhanced aerobic metabolism Fig. 2 B. This metabolic flexibility initially allows the heart to maintain ATP production even in low oxygen conditions [144]. When oxygen delivery is compromised, transcription factors like HIF-1α are upregulated to conserve oxygen by supressing mitochondrial function, while simultaneously stimulating glucose uptake and glycolysis [145]. In compensatory cardiac hypertrophy a response to acute pressure elevation, as seen in CKD, the interaction of nuclear effectors (such as through the Hippo pathway) mediates GLUT1 gene upregulation [146]. Furthermore, elevated glucose utilization strongly predicts cardiac hypertrophic and hemodynamic stress [147]. Accordingly, due to pressure overload, reduced expression of pyruvate kinase muscle isozyme (PKM1) exacerbates cardiac fibrosis and dysfunction in the failing heart. This is associated with lower heart mitochondrial respiration and ATP production [147]. On the other hand, studies using empagliflozin (an antihyperglycemic drug) have shown that shifting energy substrate utilization from glucose to the ketone bodies, FA and branched-chain amino acids increases ATP content and myocardial work efficiency, ultimately improving cardiac function and structure [147]. Together, these studies suggest that the modification from OXPHOS to glycolytic metabolism during reno-cardiac pathology contributes to heart function loss and pathology development.

3. Role of GSH in the mitochondrial alterations from AKI to CKD and reno-cardiac disease

AKI and CKD are characterized by oxidative stress [148,149], with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), mitochondrial ETS, and Krebs cycle dehydrogenases being the main ROS sources [98,116,148]. Mitochondria, peroxisomes, and the endoplasmic reticulum (ER) also produce ROS at lower concentrations as part of their normal metabolism, which act as second messengers in several pathways [150,151]. For example, intracellular fluctuations of H₂O₂ (1–100 nM) induce changes in cell metabolism, a phenomenon known as “oxidative eustress” [99,152]. In contrast, in “oxidative distress,” higher H₂O₂ levels (>100 nM to μM) promote unspecific oxidation of biomolecules, cell damage, and death [152,153]. Therefore, ROS must be maintained in “the redox tone”, which varies widely between cell compartments [152,153]. For example, in the cytosol, the H₂O₂ concentration is 80 nM, compared to 5–20 nM in the mitochondrial matrix, and 700 nM in the ER lumen [154,155].

As is shown in Fig. 3, the redox tone mediates H₂O₂-dependent cell signaling by changes in the GSH/GSSG, inducing protein modification, especially in Cys [156,157]. Cys represent only 2 % of total amino acids but are the most conserved in peptide sequences [149], frequently found in the catalytic core, chelating transition metal centers, and protein surface [99,158]. Interestingly, mitochondria are the most free Cys-enriched organelles (60–90 mM of thiol residues) [159], which regulates factors involved in energy metabolism (see Fig. 3) and biogenesis [31,99,160].

3.1. The GSH/GSSG ratio at mitochondria

The tripeptide GSH is the most abundant low-molecular weight antioxidant in cells, reaching intracellular concentrations of 0.5–30 mM and extracellular concentrations of 2–20 μM [161,162]. GSH is ionized at physiological pH, necessitating specific transporters and generating varying GSH concentrations between organelles [161,163]. Free GSH is in equilibrium with its oxidized form, GSSG. Therefore, the GSH/GSSG ratio can be an indicator of redox state, defined by the glutathione redox potential (E_GSH/GSSG) [163]. The cytosol has a high GSH/GSSG ratio (10–50) and total concentrations ranging from 10 to 30 mM [163,164]. Mitochondria display independent GSH redox states, import systems, glutathione-utilizing enzymes, and a mechanism of GSSG reduction between the matrix and the intermembrane space (IMS). In the IMS, the GSH/GSSG ratio is similar to that of the cytosol, while it is more reduced in the matrix (GSH concentration: 10–14 mM) [165,166]. Because mitochondrial compartments lack the enzymes to synthesize GSH de novo, it must be imported from the cytosol. As is shown in Fig. 3, a mitochondrial pore called the voltage-dependent anion channel (VDAC) and the translocase of the outer membrane (TOM) are associated with GSH transport through the outer mitochondrial membrane (OMM) [163,167]. Meanwhile, GSH transport in the inner mitochondrial membrane (IMM) is mediated by the oxoglutarate (OGC) and the dicarboxylate (DIC) carriers [168]. In contrast, mitochondria export GSH through the IMM is mediated by the ABC transporter of mitochondria 1 (ATM1), by the extrusion of GSSG or glutathione adducts [169]. Both compartments possess their own GSSG reduction system. The glutathione reductase (GR) is localized in both IMS-cytosol and mitochondrial matrix [170]. However, glucose 6-phosphate dehydrogenase (G6PDH) is find in cytosol but not in the matrix. Conversely, NADPH is generated in the matrix by the malic enzyme, the methylene tetrahydrofolate dehydrogenase (MTHFD2), and the nicotinamide nucleotide transhydrogenase (NNT) [[171], [172], [173]]. The NNT enzyme uses the ΔΨm to reduce NADPH from NADH equivalents [173,174]. Notably, the highest NNT expression is in the heart and kidneys (i.e., tubular epithelial cells) [174].

3.2. The GSH metabolism at the kidney

Most de novo GSH synthesis occurs in the liver [175]. However, GSH synthesis also occurs in the kidney, in a two-step pathway (Fig. 4A), with the first step catalyzed by the glutamate cysteine ligase (GCL) and the second by the glutathione synthetase (GS) [162]. The GCL catalyzes the rate-limiting step in GSH biosynthesis and is composed of a heavy catalytic subunit (GCLC) of 73 kDa and a regulatory subunit (GCLM) of 31 kDa. The catalytic subunit is inhibited by GSH in a feedback regulation mechanism and allosterically activated by the heterodimeric formation with GCLM [176,177]. The activity of GCL is post-transcriptionally regulated by phosphorylation and glycation [178,179]. At the transcriptional level, ROS and other electrophiles triggers GCLC and GCLM expression through the nuclear factor erythroid 2-related factor (Nrf2), the mitogen-activated protein kinase (MAPK), and the musculoaponeurotic fibrosarcoma (MAF) families dependent pathways [[180], [181], [182], [183]]. Additionally, inflammatory signals like the IKKβ–NF–κB pathway regulate GCLC/GCLM [184]. On the other hand, GS is a homodimer, only controlled by transcriptional expression [162,185].

In the kidneys, renal filtration and reabsorption remove 80 % of GSH plasma levels, especially in the proximal tubule [186]. Approximately 50 % of this extraction is mediated by the sodium/carboxylate cotransporter 3 (NaC3) and by organic anion transporters 1 and 3 (OAT1/3) [187]. The kidney also possesses the highest levels of γ-glutamyl transferase (GGT), an enzyme that initiates the extracellular catabolism of GSH- adducts [163,188]. GGT is ocated on the plasma luminal membrane (Fig. 4 A), where it hydrolyses GSH into glutamic acid and cysteinyl-glycine, which is cleaved by cell surface dipeptidases, releasing Cys [188]. Then, Cys is reabsorbed by Cys-related transporter “rBAT-b(0,+)AT” [189]. Meanwhile, multidrug resistance-associated protein 2/4 (MRP) is in charge of the renal efflux of a wide range of GS adducts [163,190,191].

In line with the idea of a greater need for ROS control mechanisms in mitochondria-rich segments [40,112,113], the cortex needs a higher GSH synthesis capacity. Consequently, GSH concentration is highest in the renal cortex and progressively decreases towards the medulla [184]. Furthermore, the GSH/GSSG ratio, GSH import systems, glutathione-utilizing antioxidant enzymes, GS-adducts extrusion systems, and mechanism of GSSG reduction are higher in cortical segments than in the outer medulla and the lowest in the inner medulla [174,187,188,192,193].

3.3. The GSH metabolism at the heart

Similar to the kidney, the high energy demand of the heart makes cardiomyocytes extremely dependent on mitochondrial oxidative metabolism [194,195], favoring the continuous production of ROS. However, under physiological conditions, the intracellular GSH levels, the activity of GSH-dependent antioxidant enzymes, and the capacity of GS-adducts extrusion systems have been reported to be lower than in other tissues [[196], [197], [198], [199]]. The GSH/GSSG ratio maintenance in the cardiomyocyte mainly depends on two mechanisms (Fig. 4 B). The first one is based on preventing GS-adducts accumulation by MRP1-dependent extrusion, which are later cleaved in the extracellular medium to release Gly and Glu, which are reabsorbed into the cell to support GSH synthesis [198,200,201]. In the second mechanism, GSSG or adducts are intracellularly reduced to GSH by the GR-PPP dependent pathway [200,202]. Meanwhile, IMM transport is also regulated by OGC and the DIC carriers, which are highly expressed in the myocardial tissue [203].

Additionally, a new intracellular heart GSH degradation pathway has been recently proposed. As shown in Fig. 4 B, GSH is intracellular degraded by the cytoplasmic glutathione specific γ-glutamyl cyclotransferases 1 and 2 (Chac1/2), releasing 5-oxoproline and Cys-Gly. Both products are later cleaved by 5-oxoprolinase (OPLAH), and Cys-Gly dipeptidase 2 (CGDP2) respectively, thereby releasing the components for GSH synthesis [204,205]. Because Chac1/2, are specific for GSH, an increase in their activities triggers GSH/GSSG reduction, oxidative stress and increases in calcium cytosol levels, thereby favoring heart failure [206]. Furthermore, Chac1 knockdown reduces ferroptosis and cell injury in cardiomyocytes [207]. Additionally, the heart GSH redox homeostasis is easily disrupted under pathological conditions, making cardiomyocytes especially susceptible to oxidative stress [198]. Several studies showed that pathological damages to the myocardium is associated with an early reduction in GSH synthesis, GS-adducts extrusion and GSSG reduction systems [202,208,209], leading to a lower GSH/GSSG ratio and limiting antioxidant enzyme capacity [34,200]. Furthermore, GSH depletion and GPX4 activity reduction are key points in promoting cell death mechanisms in cardiomyocytes, particularly ferroptosis [200,210]. Therefore, understanding heart GSH regulation systems and how to restore redox balance has gained importance in the development of new therapies to prevent myocardial injury [200].

3.4. NAC in mitochondrial GSH alterations and mitochondrial target antioxidants in AKI, CKD and reno-cardiac disease

AKI and CKD exhibit cytosolic and mitochondrial GSH/GSSG ratio reduction in proximal tubule cells from early injury in several models [35,61,83,96,97,211]. Although information on CRS syndrome remains limited, recent studies revealed decreased GSH/GSSG ratios and increased pro-oxidant states in cardiomyocytes and cardiac mitochondria, potentially contributing to heart damage [34,108,212]. The GSH/GSSG ratio reduction stimulates the S-glutathionylation (RS-SG) removal activity of mitochondrial glutaredoxin 2 (Grx2), favoring renal damage [35]. Enzymatic RS-SG protects proteins from the irreversible oxidation of Cys residues under oxidative stress [99,160]. Furthermore, it triggers three processes to recover redox balance: First, the reduction in the activities of the Krebs cycle, ETS, and β- β-oxidation. Second, the reduction of ROS production by these pathways. Third, the pentose phosphate pathway is increased, supporting NADPH and GSH/GSSG ratio restoration [34,35,99,160,213].

In this regard, GSH synthesis inducers have recently been studied to preserve mitochondrial homeostasis and RS-SG levels [35,61,[214], [215], [216], [217], [218]]. Among them, NAC is widely used in experimental models and clinical studies, where it positively affects renal function in AKI and CKD [[214], [215], [216], [217], [218]] and the heart in CRS syndrome [34,[219], [220], [221]]. Furthermore, NAC is perfect for replenishing GSH levels under GSH deficiency conditions, without changing the GSH levels under normal conditions [176,222] and has been proposed as a RS-SG regulator [34,35,61,222]. In AKI and CKD progression, NAC administration reduces renal damage markers [35,61,223,224]. These protective effects have been related to glomerulus [223] and proximal tubule preservation [35,61,225], conservation of renal hemodynamics [35,61,223,226], and ROS and angiotensin II (Ang II) levels reduction [35,61,216,[227], [228], [229]]. Meanwhile, in CRS, NAC administration has shown similar effects, restoring GSH levels, GSH/GSSG ratio, blood flow, and the activity of antioxidant enzymes, and reducing inflammation and mitochondrial ROS production in the heart [34,220,221]. Interestingly, the protective effects are also linked to the preservation of RS-SG levels, and CI and CIII activity by mitochondrial GSH/GSSG ratio restoration in kidney and heart [34,35,61,[230], [231], [232]]. NAC also decreases apoptotic induction, the release of mitochondrial damage-associated molecular patterns (DAMPs), and the activation of the nucleotide-binding oligomerization domain-like receptors (NLR)-family pyrin domain containing 3 (NLRP3) inflammasome and the NF-κB pathways [228,233,234]. Consequently, NAC reduces the pro-inflammatory cytokines release [221,232,[235], [236], [237]] and positively regulates the composition and release of EVs [238], mechanisms associated with mitochondrial regulation.

In AKI, CKD and CRS mitochondrial dysfunction, specifically excessive mitochondrial ROS overproduction and fission induction lead to apoptosis and tissue damage [34,35,65,96,239]. Therefore, antioxidants compounds that target these organelles in a specific form have been developed to prevent this mitochondrial damage. For example, the mitochondrial-targeted coenzyme Q10 (MitoQ) has an antioxidant capacity that depends on ΔΨm induced localization. It reduces mitochondrial ROS and restores ATP levels in preclinical AKI models [240,241], and during nephrotoxicity [242]. The effect is mediated by stimulating sirtuin 3 (SIRT3) activity and reducing cell apoptosis [241]. It is important to note that MitoQ effects have also been detrimental in proximal tubule cells. For example, it induces mitochondrial swelling and depolarization independently of oxygen consumption rate [243]. Thus, the adverse impact of MitoQ has been not related to its antioxidant activity. Instead, it has been associated to its capacity to induce ΔΨm depolarization due to the insertion of an alkyl chain [243].

Like wise, MitoTEMPO is other mitochondria-targeted nitroxide whose activity mimics to the SOD enzyme. In cancer, MitoTEMPO inhibits glycolysis by reducing ROS production [244]. In CKD, MitoTEMPO attenuates renal injury by preserving mitochondrial function and decreasing mitochondrial ROS production [245]. On the other hand, elampretid (also called MTP-131) is a mitochondrial-targeted peptide that binds to cardiolipin and replenishes mitochondrial function. It targets and concentrates in the IMM, where several enzymes produce ROS. In addition, this peptide scavenges ROS and prevents mitochondrial permeability transition pore opening and cytochrome C release. Also, it has been widely used for treating cardiac and renal diseases [245]. It has been reported that MitoTEMPO can decrease mitochondrial superoxide production in the heart and the kidney during diabetic kidney disease by regulating cardiolipin remodeling [246]. In addition, during heart failure with reduced ejection fraction, elampretide favored left ventricular volumes without having adverse effects [247]. However, mitochondrial bioenergetics in the heart was not evaluated in this condition. Interestingly, in another study, elampretide reduced the expression of TGF-β1, NOX4, and the activation of p38 MAPK pathway, probing its protective antioxidant effect against high glucose-induced renal injury [240]. During atherosclerotic renal artery stenosis in patients, elampretide improved renal function, oxygenation, and renal blood flow [248]. This component has not had controversial findings.

Visomitin (SKQ1) compounds are mitochondria-penetrating positively charged cations whose primary function is inhibiting mitochondrial ROS. Like MitoTEMPO, SKQ1 inhibits cell damage triggered by H₂O₂ [249]. In addition, this compound reverses the downregulation of the antioxidant defense and enzymes. In AKI, this antioxidant improves renal morphology by inhibiting ferroptosis and mitochondrial dysfunction [250]. Furthermore, SKQ1 has been shown to be protective in cardiac hypertrophy by improving antioxidant defense and regulating mitochondrial H₂O₂ levels [251]. Many other antioxidants not direct directed to mitochondria have been also proven to be efficient in reduce AKI and CKD induced mitochondrial impairment [35,65,83,252,253]. These effects are associated with decreased ROS, increasing OXPHOS capacity and apoptosis reduction. Between them found sulphoraphane, NAC, resveratrol, curcumin, quercetin, and α-mangostin [35,65,83,252,253].

3.5. Mitochondria ROS and the activation of pro-inflammatory mechanisms

In AKI, the initial injury leads to kidney inflammation as part of the reparatory mechanisms [254]. However, the persistence of the damage leads to CKD development [255,256]. Renal inflammation results from the activation of several pathways that are enhanced by ROS activation of the mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase (PI3K), renin-angiotensin- aldosterone system (RAAS) and NF-κB, pathway, increasing pro-inflammatory genes transcription [256,257] and DAMPs production [[258], [259], [260]]. Meanwhile, cell DAMPs are released and recognized by the toll-like (TLRs) and NLR receptors of target cells [237,258], including mitochondrial DAMPs, and can be packaged and transported by EVs to target cells [98,261,262]. ROS also induces the NRLP3-mediated release of pro-inflammatory EVs in podocytes [263].

Experimental AKI may induce increased left ventricular end-diastolic pressure (LVEDP) and cardiac fibrosis [264]. This phenomenon is intricately linked to the inflammatory cascade triggered by the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, which are associated with mitochondrial depolarization, ETS reduction, increased ROS production, and mitochondrial fission fragmentation [12,34,46,108,265,266]. The increase in TNF-α also triggers cardiac fibrosis by stimulating the extracellular matrix protein production (i.e., collagen), leading to myocardial stiffening and impaired function. It also promotes cardiac hypertrophy through the activation of NF-κB and MAPKs, contributing to cardiac remodeling and dysfunction [267]. Meanwhile, IL-6 stimulates cardiac hypertrophy by activating the JAK/STAT pathway. It also encourages fibrosis by upregulating TGF-β and CTGF. In this context, after 24 h of renal I/R, an impairment of OCR and ECAR is observed in myocardial tissue, along with cytochrome B release and cleaved caspase-3 [264,268]. Later, at 48h, Gal-3 expression increases in cardiac cells, accompanied by MCP-1 and CD68⁺ infiltrating macrophages [265], which reduces CIII and CIV activity and NRF1 nuclear translocation [269]. After 72h, cardiomyocytes swelling appears, and plasma BNP and Troponin T are significantly elevated. Meanwhile, cardiac Akt/mTOR signaling and mitochondrial bioenergetics are impaired, leading to reduced ATP production, inducing apoptosis, and ferroptosis [270,271]. In contrast, the anti-inflammatory molecule Klotho prevents an elevation of IL- 6, IL-1β, and TNF-α, and improves the calcium dysfunction of cardiomyocytes, which is associated with attenuated cardiac hypertrophy in AKI mice [272].

In addition, oxidative stress participates in the myocardial damage associated with types 3 and 4 CRS. The mtROS release triggers the NLRP3 inflammasome/IL-1β/IL-18 activation, by promoting the dissociation of thioredoxin-interacting protein (TXNIP) from thioredoxin (TRX) in both kidney and heart [46,273]. Activation of NOX4 also mediates pyroptosis, increases mitochondrial antiviral signaling protein (MAVS) [274,275], and diminishes the SIRT3 activity, SOD2 levels, and the GSH/GSSG ratio [276]. Consequently, this renal pro-oxidative state triggers the production of mitochondrial DAMPs and promotes the release of mitochondrial EVs (MitoEVs). The MitoEVs can carry mtDNA, rRNA, tRNA, mitochondrial proteins, including respiratory chain protein complexes, and intact mitochondria [277]. Interestingly, the increase in mtDNA in a CKD environment has been associated with cardiac hypertrophy, likely due to the activation of the cGAS-STING/TBK1/NF-κB pathway [278]. Similarly, patients under hemodialysis show a higher number of mtDNA copies in plasma, activation of TLR9-dependent pro-inflammatory signaling, and cardiovascular injury [279]. Increased MitoEVs are also found in chronic HF and cardiac ischemia [280].

4. Mitochondrial biogenesis impairment in CKD, AKI, and reno-cardiac disease

The AMPK-SIRT1/3-PGC-1α axis emerges as a central hub in mitochondrial biogenesis regulation. Metabolic reprogramming correlates with AMPK-SIRT1/3-PGC-1α-mediated mitochondrial biogenesis downregulation and increases inflammation [35,63,65,[78], [79], [80],281]. The AMPK/PGC-1α pathway is strongly regulated by SIRT 1 and 3 (Fig. 5), and PGC-1α stimulates the gene expression of SIRT3 [282,283]. SIRTs are NAD⁺-dependent histone deacetylases consisting of 7 members. Specifically, SIRT3 resides in the mitochondria, and SIRT1 is found in both the nucleus and the cytosol [257]. SIRTs are also important regulators of redox signaling [32]. In this regard, overregulation of SIRT1 and SIRT3 restores OXPHOS (Fig. 5), which reduces mitochondrial ROS production during renal damage and CRS. Upregulation of SIRT3-induced PGC-1α increases the expression of ROS-detoxifying enzymes and ETS subunits [230,282,283].

Fig. 5 — **NAC Induction of the AMPK-SIRT1/3-PGC-1α Pathway.** N-acetylcysteine (NAC) activates multiple targets within the AMPK-SIRT1/3-PGC-1α pathway, promoting cryoprotection. Activation of this pathway induces mitochondrial biogenesis and enhances the activity of OXPHOS enzymes, preserving mitochondrial mass. It also induces the overexpression of antioxidant enzymes, maintaining mitochondrial redox balance. Additionally, this pathway inhibits the activation of NF-κB, NLRP3, and TGF-β pathways induced by inflammatory mediators. This prevents PGC-1α inhibition and subsequent fibrotic processes. The dotted green lines symbolize the sites of action of the NAC. Ac: acetylation; AMPK: AMP-activated protein kinase; ARE: antioxidant response elements; DAMPs: damage-associated molecular patterns; GPx4: glutathione peroxidase; GR: glutathione reductase; NAC: N-acetylcysteine; NF-κB: nuclear factor kappa B; NRFs: nuclear respiratory factors; Nrf2: nuclear factor erythroid 2–related factor 2; NRLP3: NACHT, LRR, and PYD domains-containing protein 3; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen spices; mtROS: mitochondrial; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator; PPARs: peroxisome proliferator-activated receptors; SIRT1: sirtuin1; SIRT3: sirtuin3; SOD2: superoxide dismutase 2; TGF-β: transforming growth factor-beta. *Figure created using BioRender*.com (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).

The AMPK-SIRT1/3-PGC-1α axis regulates the gene expression of mitochondrial transport, fatty acid oxidation, OXPHOS, and biogenesis proteins [284]. Since PGC-1α expression is suppressed during the AKI, CKD, and CRS transition by TGF-β and Smad-mediated pathways [34,211,[285], [286], [287]], this effect leads to significant oxidative stress. Likewise, SIRT3 overexpression in AKI promotes autophagy, preventing tubular cell apoptosis and the accumulation of pro-inflammatory cytokines in the kidney [288]. Interestingly, AMPK-SIRT1activation inhibits NF-KB and the expression of the NLRP3 inflammasome components, caspase-1, IL-1β, and gasdermin D in mice with diabetic nephropathy [289]. Another pathway related to SIRT1 during CKD is the C-Jun N-terminal kinase (JNK) pathway. JNK promotes inflammation, cell death, and fibrosis in CKD [290,291]. Conversely, preventing the joint signaling of JNK and Smad3 avoids the downregulation of PGC-1α in myofibroblasts and proximal tubular cells, thus preventing mitochondrial dysfunction in CKD and CRS [292]. Indeed, restoring mitochondrial biogenesis by means of antioxidants or PGC-1α agonists prevented inflammatory processes and fibrosis in AKI, CKD and CRS [34,35,55,61,293].

In this line, a reduction in the expression of mitochondrial biogenesis factors is observed in the kidney and in the heart (i.e., SIRT1, SIRT3, PGC1a, NRF-1, NRF-2, CPT1A, ATP5A) for both type-3 and -4 CRS [34,35,72]. In particular, the AMPK/SIRT1/3/PGC-1α axis emerges as a central component in coordinating mitochondrial biogenesis at the cardiac level [[294], [295], [296]], regulating the expression of genes encoding mitochondrial proteins [297,298] and also upregulating antioxidant enzymes, enhancing cardiomyocyte viability [299]. Of interest, the subcellular localization of AMPK, SIRT1/3, and PGC1a has been observed in both mitochondria and nuclei, suggesting a contribution of these organelles to maintaining mitochondrial homeostasis [300,301]. The most important changes reported in the proteins involved in this pathway are summarized in Table 1.

Table 1.

Mitochondrial homeostasis factors in CRS type 3 and 4. Variations of proteins [p-AMPK (phosphorylated AMP-activated protein kinase), PGC1a (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, SIRT1/3 (Sirtuins 1 and 3), NRF1/2 (Nuclear Respiratory Factor 1 and 2), TFAM (mitochondrial transcription factor A), Drp1 (Dynamin-Related Protein 1), Fis1(Fission 1), Mitofusin 1 and 2 (Mfn 1/2), OPA1 (Optic Atrophy type 1), PINK1 (PTEN-induced putative kinase 1), BNIP3 (BCL2 interacting protein 3), FUNDC1 (FUN14 domain containing 1), and Microtubule-associated protein 1A/1B-light chain 3 (LC3)] of mitochondrial homeostasis are described in CRS type 3 and 4. Arrows indicate over- or down-regulation of factors. n.r., non-reported data.

	Factors	CRS Type 3		CRS Type 4		References
	Factors	Kidney	Heart	Kidney	Heart	References
Mitochondrial Biogenesis	p-AMPK	↓	n.r.	↓↑↔	↓	[[302], [303], [304], [305]]
	PGC1a	↓	↓	↓	↓↔	[30,34,35,47,72,281]
	SIRT1	↓	↓	↓	↓	[34,306,307]
	SIRT3	↓↔	↓	↓	n.r.	[34,304,306,308]
	NRF1	↓	↓	↓	↓	[34,35,47,72,281,309]
	NRF2	↓	↓	↓	↓	[35,281,310]
	TFAM	↓	↓	↓	↓	[35,47,72,281,311]
Mitochondrial Dynamic	Drp1	↑	↑↓	↑	↑↓	[30,34,281,308,311,312]
	Fis1	↑	↔↑	↔	↔	[30,35,281,313]
	Mfn1	↓	↔↑	↓	↓	[30,35,281,311]
	Mfn2	↔	↔↓↑	↓	↓	[12,34,35,281,311,312]
	OPA1	↓	↔↓	↓	↓	[34,35,281,312,313]
Mitophagy	PINK1	↑↓	↑	↑↓↔	n.r.	[34,35,83,281,314,315]
	Parkin	↑↓	↓↔	↓↔	n.r.	[34,281,[314], [315], [316], [317]]
	BNIP3	↑	↑	↑	n.r.	[34,303,318,319]
	FUNDC1	↑	↓	↑	↓	[303,313,317,320,321]
	LC3	↓↑	↓	↓↑	↓↑	[35,83,281,309,310,313,316,321]

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On the other hand, recent studies have uncovered NAC-protective effects related to mitochondrial mass preservation through Sirtuins-AMPK-PGC1-α pathway activation [35,61,230,234,236]. In experimental diabetic nephropathy, NAC was found to inhibit ferroptosis by an SIRT3-SOD2/Gpx4 dependent pathway [322]. NAC also mitigates the detrimental effects of Bisphenol A in renal ischemia-reperfusion (IRI) injury by improving SIRT3-dependent mitochondrial biogenesis [323].

Mechanistically, NAC increased AMPK levels, thereby promoting SIRT3 transcription and enhancing the antioxidant response mediated by PGC-1α and Nrf2 (Fig. 5). SIRT1 and SIRT3 activation by NAC may inhibit inflammation by oxidative stress reduction and mitochondrial biogenesis induction in CKD and CRS type 3 [34,64,79,281]. Likewise, NAC enhances SOD2 antioxidant activity in mitochondria through SIRT3-mediated deacetylation [282,323]. NAC also restores the levels of antioxidant enzymes SOD2 and GPx and the ETS complexes and Krebs cycle enzyme activities [34,324]. Importantly, stimulation of the renal AMPK/SIRT1/3/PGC-1α axis decreases mtROS production and NLRP3 inflammasome/IL-1β/IL-18 activation during AKI, CKD and CRS [34,286,288,325,326]. Thus, NAC-induced mitochondrial protection may be a potential treatment to prevent inflammation in AKI, CKD and CRS [34,64,79,281] Besides, recent studies suggest that the activation of SIRT3 occurs by direct interaction with NAC [322], creating a new range of molecular targets. As is shown in Fig. 5, NAC effects on SIRTs regulation can be diverse given its multifaceted capabilities. These findings underscore NAC's therapeutic potential in mitigating mitochondrial biogenesis and inflammation by AMPK-SIRT1/3-PGC-1α activation.

4.1. In silico interaction between NAC and SIRT1/3

The potential interaction and activation of SIRT1/3 by NAC could be tested using in silico tools like molecular docking; in this way, it is possible to have a better view of the molecular interaction between these molecular targets and the NAC, and reinforce the experimental evidence that suggests the activation of SIRT1/3 by NAC [230,234,236,286,327].

It is remarkable all the studies around the search of activating compounds for these two enzymes [323,328,329], especially for the important role than they play in CKD [282,283,288]. The activation of SIRT1/3 implies an improve of their catalytic activity without interfering with NAD⁺ interaction, taking in account this important union and for a better understand of this section we summarize the principal structural features of all the SIRTs isoforms: 1) a Rossman domain that contains the catalytic and the NAD⁺ binding amino acids, 2) a region with the amino acids that allow the union with the atom of zinc, and 3) an N and C-terminal domains with different regulatory and recognizing activity [330,331]; although SIRT1/3 have remarkable structural similarities, they show different 3D structure [332]. Therefore, the link of activation molecules when the NAD⁺ is linked will occur in different structural sites. In the case of SIRT1, the predominant interactions happen in the N-terminal domain [329,331,333], one example it is the complex SIRT1-resveratrol [333]. On the other hand, for SIRT3 the activating compounds like honokiol, binds near the NAD⁺ interacting zone. Notably, the formation of these complex has been reported to reduce damage in heart and renal diseases, making it an important therapeutic strategy [323,328,330,334,335].

To predict the main possible regions of interaction between NAC and SIRT1 and SIRT3. we used resveratrol and honokiol as positive controls [333,334] for SIRT1 (PDB ID:4ZZJ) and SIRT3 (PDB ID: 5H4D), used the PDB crystallography structure. The docking simulation was carried out using AutoDock4Zn and AutoDockTools [336], with a grid of 60 × 60 × 60 Å. The coordinates were selected based on the previous interaction with the positive controls. Chimera [337] was employed for the preparation of protein structures and figures. Finally, Spartan (Wavefunction Inc., Irvine, CA, USA) was used to optimize positive control compounds, considering the protonation form for each case.

As result, NAC has a similar union region like the resveratrol (SIRT1) and honokiol (SIRT3). The changes in the bond energies (ΔG) and the amino acids of interaction could be explained by the intrinsic molecular structure of NAC. The SIRT1-NAC complex presented a ΔG = −3.1 kcal/mol, showing the most favorable interaction in the alpha 1 (α1) and 2 (α2) helices at the N-terminal domain; the main forces observed in the complex SIRT1-NAC were van der Waals (Leu¹⁹², Ile²²⁵, Val¹⁸⁸, Trp²²¹, Met²¹⁸, Gln²²²), hydrogen bonds (Gln¹⁸⁹ and Thr¹⁸⁵), and a very stable π-anion (Try¹⁸⁵ and O⁻ of the deprotonated carboxyl group) (Fig. 6A). NAC showed some of the same amino acids of interaction showed by resveratrol (ΔG = −5.1 kcal/mol) with the main difference that resveratrol interacts more with the amino acids in the α3.

Fig. 6 — **NAC Interaction with SIRT1 and SIRT3. (A)** SIRT1: Ribbon representation of SIRT1 (PDB ID: 4ZZJ) and its complexes with NAC (yellow sticks), resveratrol (magenta sticks), and a NAD⁺ derivative (Carba-nicotinamide-adenine-dinucleotide; orange sticks). Magenta lines indicate hydrogen bonds between NAC and SIRT1. The green sphere represents a zinc atom. **(B)** SIRT3: Ribbon representation of SIRT3 (PDB ID: 5H4D) and its complexes with NAC (yellow sticks), honokiol (cyan sticks), and NAD⁺ (orange sticks). The green sphere represents a zinc atom. Magenta lines indicate hydrogen bonds. NAC may activate SIRT1 and SIRT3 through direct interaction with their structural regions. *Figure created using BioRender*.com (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).

In the case of SIRT3, the important area where NAC interacted was near the hydrophilic cavity occupied by NAD⁺ and honokiol with a ΔG = −4.6 kcal/mol. Also, it was observed that this area was mainly composed of loops. The predominant interactions were hydrogen bonds Gln²²⁸, His²⁴⁸, Thr³²⁰, Ser³²¹, Leu³²², Glu³²³, and Val³²⁴) and van der Waals forces (Glu³²⁵ and Pro³²⁶) (Fig. 6B). All these interactions could be explained by the complete deprotonation of NAC in the mitochondrial matrix. Finally, we observed that honokiol (ΔG = −6.8 kcal/mol) had a larger surface area, improving its interaction with a greater number of amino acids in the loops of this cavity. Still, the number of hydrogen bonds was lower than that of NAC, increasing the formation of a more stable complex with this compound.

Based on the obtained results, the activation of SIRT1 and SIRT3 could be initiated by NAC's direct interaction with each enzyme's structural regions. The last assumption was supported by the fact that NAC exhibited binding sites comparable to those presented by the most studied activators of each one of these enzymes. Therefore, this opens the door to uncovering new regulatory mechanisms in the mitochondrial physiology of NAC that were previously unknown.

4.2. Mitochondrial dynamics and mitophagy in CRS

Mitochondrial fusion and fission can also be compromised in type-3 and -4 CRS [294]. In AKI and CKD, dysfunctional mitochondria may release mtDNA to activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, promoting an inflammatory environment with overexpression of p-p65, p-IRF3 and TBK1, and tubular damage [308,338]. In AKI mice, alterations in cardiac mitochondrial dynamics were also evidenced by the increased expression of dynamin-related protein 1 (Drp1) and Fis1, while Mfn2 and OPA1 were decreased, leading to enhanced mitochondrial fragmentation. This phenomenon may explain the subsequent inflammatory response (i.e., increases in IL-6, MCP-1, TNFα), cellular apoptosis, and cardiac dysfunction. Notably, inhibition of Drp1 attenuated these events [12,313]. In CKD mice, cardiomyocytes showed a cytosolic increase in mtDNA, which stimulates the cGAS-STING–NF– κB pathway to favor cardiac hypertrophy [278]. They also exhibited mitochondrial fragmentation, elevated levels of Drp1, but reduced Mfn1/2, and mitophagy [30,309]. Deficiencies in PTEN-induced kinase 1 (PINK1) and Parkinson disease protein 2 (PARK2) have been correlated with mitochondrial fragmentation, ROS production, and inflammation in renal tubular cells of AKI and CKD models [339,340]. Also, PINK1/Parkin activity is crucial to protect against cardiac damage through its role in preventing mitochondrial dysfunction and the increase in ROS, which may result in oxidative damage in cardiomyocytes [341]. In I/R-induced AKI and CKD, a reduction in cardiac FUN14 domain-containing protein 1 (FUNDC1) and other key mitophagy markers such as mitochondrial-associated microtubule light chain 3II (mito-LC3II), Beclin1, and autophagy-related gene 5 (Atg5) were associated with mitochondria fragmentation [313,321].

Altogether, as shown in Fig. 7, alterations in mitochondrial homeostasis in type-3 and -4 CRS highlight the crucial role of mitochondrial dynamics in these disorders. Moreover, the underlying mechanisms in these reno-cardiac pathologies involve sympathetic hyperactivation of the SNS and RAAS, inflammation, and the production of uremic toxins. All of these could be directly or indirectly interconnected to mitochondrial dysfunction [46,342].

4.3. Activation of the neurohormonal systems

During AKI, hypoperfusion and hypovolemia reduce the mean arterial pressure (MAP) through the activation of the sympathetic nervous system (SNS) [343]. In fact, an elevation of norepinephrine (NE) was observed in critically ill AKI patients [344]. Similarly, sympathetic hyperactivity is present from the early stages of CKD, leading to a worse renal prognosis [345,346]. Also, in rodents, AKI and CKD trigger hyperactivation of the renal sympathetic nervous system, increasing NE levels [[347], [348], [349]], which impairs calcium homeostasis and mitochondrial respiration in the heart by opening mitochondrial permeability transition pores (mPTP), thus producing ROS, and releasing cytochrome C [350]. The SNS stimulation also activates β1-adrenergic receptors at the juxtaglomerular apparatus, resulting in renin upregulation and release [351,352]. The decreased renal plasma flow and NaCl delivery to the macula densa also enhance Ang II levels and expression of its AT1 receptor [30,266].

Interestingly, excessive or prolonged activation of SNS and RAAS also lead to deleterious effects on cardiovascular health [353]. In AKI and CKD models, cardiac disruption of calcium and upregulation of NE, β1-adrenergic receptors, and FGF-23 have been described [266,354,355]. These responses mediate HF and arrhythmia. Also, AngII via the AT1 receptor activates NOX2 and NOX4, to elevate ROS and reduce the antioxidant defense, contributing to oxidative stress and heart mitochondrial damage [356,357]. However, the administration of melatonin, an enhancer of mitochondrial biogenesis by activating the AMPK/SIRT1/PGC1a axis, reverses these abnormalities [30,358,359]. As expected, atenolol, losartan, and enalapril improve cardiac structure and function after AKI by blocking SNS or RAAS hyperactivation [266].

4.4. Release of uremic toxins

The European Uremic Toxins Working Group (EUTox) has cataloged 146 substances that may accumulate in the body due to a reduced renal clearance, termed uremic retention solutes (URS). Currently, 130 URS are detailed in the EUTox database and some of them are classified as uremic toxins (UTs) [360,361]. The toxicity of these molecules affects numerous cellular processes, including mitochondrial respiration. Roughly, 25 % of the UTs may affect mitochondrial function, and mitochondria also serve as a provider of these molecules [362]. In particular, gut-derived UTs (i.e., indoxyl sulfate (IS), p-cresyl sulfate (pCS), indole-3-acetic acid (IAA)) are associated with mitochondrial dysfunction and cardiovascular complications arising from both AKI and CKD [[362], [363], [364]] Administration of IS and IAA to isolated mitochondria altered OXPHOS and the activity of complex III and IV [107]. Also, IS and pCS reduced PGC1a, Mfn2, and Mfn1 while upregulating Drp1, resulting in ROS deposition [365,366]. IS also promotes endoplasmic reticulum stress (ERS) and the subsequent apoptosis of cardiomyocytes [367]. An elevation of IS after I/R-induced AKI is correlated with acute cardiac dysfunction in a pro-oxidant, proinflammatory, and proapoptotic context. This scenario is partially reversed by AST-120, an oral charcoal adsorbent with the capacity to neutralize indole [368]. Furthermore, systemic therapy with endothelial progenitor cells (EPC) that prevent renal injury and lower plasma IS levels mitigated cardiac dysfunction [369].

Similarly, an independent association has been observed between IS and left ventricular hypertrophy in patients and models of CKD [370]. IS increases ROS and decreases SIRT1 activity through the aryl hydrocarbon receptor (AhR)/NADPH oxidase pathway [371,372]. IS also activates NLRP3 via the AhR/NF-κB pathway in the cardiac failure associated with CKD [373]. Activation of AhR is related to the upregulation of proinflammatory molecules and the downregulation of fatty acid oxidation and mitochondrial biogenesis [374]. Moreover, IAA stimulated the AhR/NF-κB pathway, leading to cardiac oxidative stress and inflammation in patients with CKD [375]. Interestingly, stimulation of cardiac cells with uremic serum from CKD patients induces mitochondrial fragmentation and dysfunction in the heart [376]. Lastly, the accumulation of pCS after CKD augments the NADPH oxidase activity and ROS, contributing to cardiac apoptosis and diastolic dysfunction [377].

5. Final remarks

The heart and kidney, the organs with the highest mitochondrial density, share a close intercommunication vital for maintaining mitochondrial homeostasis and ensuring proper function. Mitochondrial bioenergetics and redox imbalances are intrinsically linked to the progression from AKI to CKD. Recent evidence reveals that similar alterations in cardiac tissues are key in the pathways involved in CRS type 3 and 4 developments.

Pathological bioenergetic alteration in both organs are characterized by metabolic reprograming from oxidative to anaerobic metabolism. This leads to the decrease in Krebs cycle, β-oxidation and ETS activity and metabolism, as well as its intermediary metabolites. In the kidney, the high dependence of the mitochondrial β-oxidation and the inability to use the glycolytic pathway in PCT decreases gluconeogenesis and severely impacts the glucose supply to medullary segments. This favors a global decrease in ATP levels and ΔΨm depolarization, processes that enhance oxidative stress and the release of cardio-renal mediators by renal tissue. Although the heart's greater glycolytic capacity allows for the early ATP level compensation, experimental evidence in the CRS type 3 and 4 demonstrates that this metabolic reprograming from β-oxidation to glycolysis finally induces an energy crisis, promoting cell death, inflammation and cardiac remodeling leading to dysfunction.

Mitochondrial impairment is also linked with the redox imbalances as a result in the increase in ROS production by this organelle. In both organs this pro-oxidant state is strongly linked to the reduction in the activity of the Krebs cycle and ETS. While in the physiological context, the high capacity of GSH-dependent antioxidant systems and the high de novo GSH synthesis capacity in the kidney, allow for facing redox imbalance, in AKI and CKD GSH/GSSG ratios rapidly decrease in cytosolic and mitochondrial compartments. This induces a reduction in the RS-SG protective mechanism, further impairing bioenergetic pathways, especially ETS. Moreover, GSH depletion promotes several ROS-induced inflammatory pathways, enhancing renal secretion of pro-inflammatory cytokines and EVs. This redox imbalance is also observed from early stages in CRS, associated with the lower capacity of GSH-dependent antioxidant system in the heart. Furthermore, recent evidence suggests that RS-SG loss also impairs OXPHOS in cardiomyocytes.

Finally, mitochondrial redox and bioenergetics impairments are closely related to the downregulation of the AMPK-SIRT1/3-PGC-1α axis, reducing mitochondrial biogenesis in the transition from AKI to CKD and CRS. As shown, increased ROS levels downregulate mitochondrial biogenesis proteins reducing mitochondria mass and antioxidant gene expression and enhancing pro-inflammatory pathways and cell death in cardiac and renal tissues. In this regard, the use of antioxidants that induce GSH synthesis RS-SG levels has emerged as an integral strategy to preserve mitochondrial bioenergetics and redox homeostasis by activating several targets in AMPK-SIRT1/3-PGC-1α axis. This strategy has shown promise in reducing renal damage in the AKI to CKD transition, as well as the release of pro-inflammatory cytokines and the increase in cardio-renal connectors, like EVs release from the kidney. Antioxidants like NAC have been shown to activate AMPK and SIRTs, enhancing mitochondrial biogenesis, which inhibits metabolic reprogramming, inflammation and oxidative in CRS type 3 and IV. Although this pathway has been recently studied in AKI an CKD, and NAC effects on AMPK-SIRT1/3-PGC-1α axis have been shown to be diverse given its multifaceted capabilities, the elucidation of the mechanism states could be very useful to expose molecular targets that prevent mitochondrial alterations that favor the CSR. However, deeper studies basic and clinic levels are still necessary in this field for the development of novel treatment strategies.

In conclusion, the intricate interplay between mitochondrial dysfunction, bioenergetic alterations, and redox imbalances in both the heart and kidney plays a pivotal role in the progression from AKI to CKD and the development of CRS. The shift from oxidative to anaerobic metabolism, coupled with compromised redox balance and disrupted mitochondrial biogenesis, fuels a vicious cycle of inflammation, and cellular damage in both organs. While antioxidants like NAC have shown promise in mitigating these effects by targeting the AMPK-SIRT1/3-PGC-1α axis, further research is needed to fully elucidate the underlying mechanisms and explore novel therapeutic strategies to prevent mitochondrial dysfunction and its detrimental consequences in reno-cardiac pathologies.

Funding

Open Access funding for this article was supported by the Instituto Nacional de Cardiología Ignacio Chávez. Partial funding for the results presented in this review was provided by Fondos de Gasto Directo Autorizados a la Subdirección de Investigación Básica del Instituto Nacional de Cardiología Ignacio Chávez (protocol number 21-125) and Consejo Nacional de Humanidades, Ciencia y Tecnología (CONAHCyT; Grants CBF2023-2024-190 and CF-2023-I-1083).

CRediT authorship contribution statement

Jairo Lumpuy-Castillo: Writing – review & editing, Writing – original draft, Visualization, Investigation. Isabel Amador-Martínez: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Miriam Díaz-Rojas: Writing – original draft, Software, Methodology, Investigation, Formal analysis, Conceptualization. Oscar Lorenzo: Writing – review & editing, Supervision, Formal analysis, Conceptualization. José Pedraza-Chaverri: Writing – review & editing, Supervision, Resources, Funding acquisition. Laura Gabriela Sánchez-Lozada: Writing – review & editing, Writing – original draft, Supervision, Resources, Funding acquisition, Conceptualization. Omar Emiliano Aparicio-Trejo: Writing – review & editing, Writing – original draft, Visualization, Supervision, Resources, Project administration, Methodology, Funding acquisition, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Isabel Amador-Martínez is a student in the Programa de Doctorado en Ciencias Biológicas at Universidad Nacional Autónoma de México (UNAM). She was a recipient of the fellowship 780369 from CONAHCyT.

Contributor Information

Jairo Lumpuy-Castillo, Email: jairo.lumpuy@estudiante.uam.e.

Isabel Amador-Martínez, Email: amador_i@ciencias.unam.mx.

Miriam Díaz-Rojas, Email: diaz.530@osu.edu.

Oscar Lorenzo, Email: olorenzo@fjd.es.

José Pedraza-Chaverri, Email: pedraza@unam.mx.

Laura Gabriela Sánchez-Lozada, Email: laura.sanchez@cardiologia.org.mx.

Omar Emiliano Aparicio-Trejo, Email: omar.aparicio@cardiologia.org.mx, emilianoaparicio91@gmail.com.

Data availability

No data was used for the research described in the article.

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Data Availability Statement

No data was used for the research described in the article.

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PERMALINK

Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition

Jairo Lumpuy-Castillo

Isabel Amador-Martínez

Miriam Díaz-Rojas

Oscar Lorenzo

José Pedraza-Chaverri

Laura Gabriela Sánchez-Lozada

Omar Emiliano Aparicio-Trejo

Abstract

Graphical abstract

Highlights

1. Introduction

2. Mitochondrial bioenergetics impairment and metabolic reprogramming from AKI to CKD and reno-cardiac diseases

Fig. 1.

2.1. Lipid accumulation and reduction of the fatty-acid β-oxidation in reno-cardiac disease

2.2. Alterations of the Krebs cycle and OXPHOS

Fig. 2.

2.3. Modification of glycolysis and gluconeogenesis

3. Role of GSH in the mitochondrial alterations from AKI to CKD and reno-cardiac disease

Fig. 3.

3.1. The GSH/GSSG ratio at mitochondria

3.2. The GSH metabolism at the kidney

Fig. 4.

3.3. The GSH metabolism at the heart

3.4. NAC in mitochondrial GSH alterations and mitochondrial target antioxidants in AKI, CKD and reno-cardiac disease

3.5. Mitochondria ROS and the activation of pro-inflammatory mechanisms

4. Mitochondrial biogenesis impairment in CKD, AKI, and reno-cardiac disease

Fig. 5.

Table 1.

4.1. In silico interaction between NAC and SIRT1/3

Fig. 6.

4.2. Mitochondrial dynamics and mitophagy in CRS

Fig. 7.

4.3. Activation of the neurohormonal systems

4.4. Release of uremic toxins

5. Final remarks

Funding

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgments

Contributor Information

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

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