Fig 5 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Pink1-or Park2-deficiency deteriorated renal interstitial fibrosis after UUO. Wild-type, Pink1-KO, or Park2-KO mice were subjected to sham-operation or ligation of the left ureter, the left kidney was collected 7 days after UUO. (A) Representative images of masson's trichrome staining of kidneys sections and (B) quantitative analysis of fibrotic area (n = 4 per group). Scale bar, 50 μm(C) TGFβ1 expression was revealed by immunohistochemical staining of kidney sections, and (D) the quantitative data were shown (n = 4 per group). Scale bar, 50 μm. (E) Immunoblot analysis of protein level of α-smooth muscle actin in lysates of kidney
Source publication
Mitophagy is a principle mechanism to degrade damaged mitochondria though PARK2-dependent or PARK2-independent pathway. Mitophagy has been identified to play an important role in acute kidney disease, whereas its role in renal fibrosis remains ill-defined. We sought to investigate the involvement and regulation of mitophagy in renal tubular epithel...
Similar publications
This study aims to study the current situation, hot spots and development trends of Sanqi total saponins in the prevention and treatment of renal fibrosis through a visual map, in order to provide a direction and trend for the research of traditional Chinese medicine on the prevention and treatment of renal fibrosis. Method: By using CiteSpace visu...
Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) leading to renal fibrosis, progressive deterioration of renal function, and eventually to end stage renal disease. Matrix metalloproteinases (MMPs) are known to regulate synthesis and degradation of the ECM. Earlier, we demonstrated that imbalanced MMPs pr...
Notch receptors are transmembrane proteins that are members of the epidermal growth factor-like family. These receptors are widely expressed on the cell surface and are highly conserved. Binding to ligands on adjacent cells results in cleavage of these receptors, and their intracellular domains translocate into the nucleus, where target gene transc...
Progressive tubulointerstitial fibrosis is the common final outcome for all kidney diseases evolving into chronic kidney disease (CKD), whereas molecular mechanisms driving fibrogenesis remain elusive. Retinoic acid-inducible gene-I (RIG-I), an intracellular pattern recognition receptor, is originally identified participating in immune response by...
Citations
... During acute kidney damage as well as acute heart damage, the cells of these organs are insufficient for the oxidation of fatty acids, due to which ATP is depleted and lipids accumulate in the cell, and an alternative path in the tubule cells in the kidneys for energy restoration and ATP synthesis is achieved with the help of enzymes glycolysis, while this modification in the heart has not been insufficiently researched for the time beeing [76][77][78]. ...
Despite a large amount of research on synchronous and mutually induced kidney and heart damage, the basis of the disease is still not fully clarified. Healthy mitochondria are essential for normal kidney and heart function. Mitochondrial dysfunction occurs when the clearance or process of generation and fragmentation of mitochondria is disturbed. The kidney is the second organ after the heart in the number of mitochondria. Kidney tubules are rich in mitochondria due to the high energy requirements for absorption processes of large amounts of ultrafiltrate and dissolved substances. The place of action of oxidative stress is the influence on the balance in the production and breakdown of mitochondrial reactive oxygen species . A more precise determination of the place and role of key factors that play a role in the onset of the disease is necessary for understanding the nature of the onset of the disease and the creation of therapy in the future. The narrative review integrates results found in previously performed studies which have evaluated oxidative stress participation in renocardial syndrome type 3.
... 21 This process exerts a protective effect in a variety of kidney pathophysiological processes, 22 including acute kidney injury, 23 diabetic nephropathy, 24 and tubulointerstitial fibrosis. 25 Li Shu et al. 26 demonstrated that mice with impaired mitophagy due to PINK1 or PARK2 gene knockout exhibited more pronounced kidney fibrosis compared with control subjects. Recent study has identified mTORC2 as a negative regulator of mitophagy via the mTORC2-AKT-SGK axis. ...
Background
Renal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney‐transplanted patients. While renal vascular endothelial‐mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single‐cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms.
Methods
The influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout.
Results
Our findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα‐induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3‐mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5‐mediated degradation of BNIP3 at the K130 site through K48‐linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout.
Conclusions
Consequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3‐mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.
... It is reported that mitophagy is beneficial to the repression of cell senescence [41], renal ischemia/ reperfusion injury [42] and glioma progression [43]. Also Park2-mediated mitophagy is confirmed to play a protective role in many diseases, For instance, Drp1regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction [44]. Interestingly, overactive mitophagy triggered off under certain stressful status may function as a disease contributor. ...
Up to now, there’s a limited number of studies on the relationship between PINK1/Park2 pathway and mitophagy in NAFLD. To investigate the effect of Park2-mediated mitophagy on non-alcoholic fatty liver disease (NAFLD). Oleic acid was used for the establishment of NAFLD model. Oil red-dyed lipid drops and mitochondrial alternations were observed by transmission electron microscopy. Enzymatic kit was used to test lipid content. The levels of IL-8 and TNF-α were determined by ELISA. Lenti-Park2 and Park2-siRNA were designed to upregulate and downregulate Park2 expression, respectively. The changing expression of PINK and Park2 was detected by RT-qPCR and Western blot. Immunofluorescence staining was applied to measure the amount of LC3. Successful NAFLD modeling was featured by enhanced lipid accumulation, as well as the elevated total cholesterol (TC), triglyceride (TG), TNF-α and IL-8 levels. Mitochondria in NAFLD model were morphologically and functionally damaged. Park2 expression was upregulated by lenti-Park2 and downregulated through Park2-siRNA. The PINK1 expression showed the same trend as Park2 expression. Immunofluorescence staining demonstrated that the when Park2 was overexpressed, more LC3 protein on mitochondrial autophagosome membrane was detected, whereas Park2 knockdown impeded LC3’ locating on the membrane. The transmission electron microscopy image exhibited that the extent of damage to the mitochondrial in NAFLD model was revered by enhanced Park2 expression but further exacerbated by reduced Park2 expression. Park2-mediated mitophagy could relive NAFLD and may be a novel therapeutic target for NAFLD treatment. Keywords: Non-alcoholic Fatty Liver Disease (NAFLD) • Mitophagy • PINK1/Park2 • Park2 • PINK1
... In addition, a lack of mitophagy can lead to kidney disease. PINK1 or PARK2-mediated mitophagy loss significantly increases the production of mitochondrial reactive oxygen species (mROS) and amplifies the transforming growth factor (TGF)-β1/Smad2/3 cascade, thereby accelerating renal fibrosis (Li 2020). Meanwhile, mitophagy inducer significantly delayed renal fibrosis in mice (Jin 2022). ...
Mitochondria serve as the primary site for metabolizing the three major nutrients, underscoring their pivotal role in cellular energy metabolism and the regulation of signaling pathways. Mitochondrial homeostatic imbalance is a key pathological cause of the development of many diseases. Hence, preserving mitochondrial homeostasis is vital for the normal growth and development of cells and organisms. Living organisms have evolved intricate regulatory mechanisms to ensure cellular mitochondrial homeostasis. This review focuses on recent advancements in comprehending the mechanisms responsible for maintaining mitochondrial homeostasis and addresses the current challenges in this field. We also provide an overview of the key functions of mitochondria in both physiological and pathological conditions. Emphasizing the potential therapeutic implications, we discuss strategies for preserving mitochondrial homeostasis, recognizing its significance in mitigating various health conditions.
Graphical Abstract
... 53 Furthermore, mitochondrial fission also triggers the induction of mitophagy to remove damaged mitochondria since fission induces the recruitment of Pink1 through Drp1. 54 In UUO and Nx models, high levels of Drp1 promote the upregulation of Pink1 and Parkin. 28,42,44 The recruitment of Pink1 and Parkin from the cytosol to the mitochondria is only the first step for the induction of mitophagy and are markers commonly evaluated for this process. ...
Kidney diseases are a growing health problem worldwide, causing millions of deaths. Acute kidney injury (AKI) commonly evolves into chronic kidney disease (CKD) and fibrosis, which is a feature of CKD predisposing to end-stage renal disease. Thus, treatments that avoid this transition are urgently necessary. Mitochondria are the hub energy house of the renal cells, which provides energy in adenosine triphosphate (ATP) form, commonly obtained from β-oxidation through fatty acids degradation into the mitochondrial matrix. Mitochondria are plastic organelles that constantly change according to the cell's energy requirements. For this, mitochondria carry out biogenesis, fission, fusion, and mitophagy/autophagy, processes highly regulated to maintain mitochondrial bioenergetics and homeostasis. Alterations in one or more of these processes might cause detrimental consequences that affect cell function. In this sense, it is widely accepted that mitochondrial dysfunction associated with oxidative stress plays a crucial role in developing kidney diseases. Therefore, antioxidants that target mitochondria might be an excellent strategy to ameliorate mitochondrial dysfunction, and selecting one or another antioxidant could depend on AKI or CKD requirements. This review focuses on potent antioxidants such as sulforaphane (SFN), N-acetyl cysteine (NAC), resveratrol, curcumin, quercetin, and α-mangostin in the improvement of mitochondrial function in kidney pathologies.
... The PINK1/parkin pathway mediates the autophagy clearance of DM. Mitophagic deficiency via PINK1 or PARK2 loss has been shown to drastically enhance tubular cell apoptosis and tissue damage, while increasing MD, mitochondrial ROS formation, DNA oxidative injury, and inflammation in several renal injury models (unilateral ureteral obstruction model, contrast/ cisplatin media-induced acute kidney injury model, and renal ischemia-reperfusion models) (37)(38)(39)(40). Similarly, mitochondrial fragmentation, reduced PINK and Parkin expression, and increased apoptosis were reported to occur in the tubular cells of diabetic nephropathy mice and were then reversed by increasing the expression of PINK1 and parkin via injection of mitoQ (41). ...
Background
Irradiation (IR) promotes inflammation and apoptosis by inducing oxidative stress and/or mitochondrial dysfunction (MD). The kidneys are rich in mitochondria, and mitophagy maintains normal renal function by eliminating damaged mitochondria and minimizing oxidative stress. However, whether astragaloside IV (AS-IV) can play a protective role through the mitophagy pathway is not known.
Methods
We constructed a radiation injury model using hematoxylin and eosin (HE) staining, blood biochemical analysis, immunohistochemistry, TdT-mediated dUTP nick end labeling (TUNEL) staining, ultrastructural observation, and Western blot analysis to elucidate the AS-IV resistance mechanism for IR-induced renal injury.
Results
IR induced mitochondrial damage; the increase of creatinine (SCr), blood urea nitrogen (BUN) and uric acid (UA); and the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and apoptosis in renal tissue. AS-IV administration attenuated the IR-induced MD and reactive oxygen species (ROS) levels in the kidney; enhanced the levels of mitophagy-associated protein [PTEN-induced putative kinase 1 (PINK1)], parkin proteins, and microtubule-associated protein 1 light 3 (LC3) II/I ratio in renal tissues; diminished NLRP3 inflammasome activation-mediated proteins [cleaved cysteinyl aspartate-specific proteinase-1 (caspase-1), interleukin-1β (IL-1β)] and apoptosis-related proteins [cleaved caspase-9, cleaved caspase-3, BCL2-associated X (Bax)]; reduced SCr, BUN, and UA levels; and attenuated the histopathological alterations in renal tissue. Conversely, mitophagy inhibitor cyclosporin A (CsA) suppressed the AS-IV-mediated protection of renal tissue.
Conclusions
AS-IV can strongly diminish the activation and apoptosis of NLRP3 inflammasome, thus attenuating the renal injury induced by radiation by promoting the PINK1/parkin-mediated mitophagy. These findings suggest that AS-IV is a promising drug for treating IR-induced kidney injury.
... Sham: simulated surgery; UUO: unilateral ureteral obstruction; RUUO: release of UUO; SFN + RUUO: SFN administered before RUUO. previously suggested the relevance of mitochondria in the UUO model [18,19,85], so future studies might focus on developing therapies that target mitochondria after obstruction removal. ...
Releasing unilateral ureteral obstruction (RUUO) is the gold standard for decreasing renal damage induced
during unilateral ureteral obstruction (UUO); however, the complete recovery after RUUO depends on factors
such as the time and severity of obstruction and kidney contralateral compensatory mechanisms. Interestingly,
previous studies have shown that kidney damage markers such as oxidative stress, inflammation, and apoptosis
are present and even increase after removal obstruction. To date, previous therapeutic strategies have been used
to potentiate the recovery of renal function after RUUO; however, the mechanisms involving renal damage
reduction are poorly described and sometimes focus on the recovery of renal functionality. Furthermore, using
natural antioxidants has not been completely studied in the RUUO model. In this study, we selected sulforaphane
(SFN) because it activates the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces
an antioxidant response, decreasing oxidative stress and inflammation, preventing apoptosis. Thus, we pre-
administrated SFN on the second day after UUO until day five, where we released the obstruction on the three
days after UUO. Then, we assessed oxidative stress, inflammation, and apoptosis markers. Interestingly, we found
that SFN administration in the RUUO model activated Nrf2, inducing its translocation to the nucleus to activate
its target proteins. Thus, the Nrf2 activation upregulated glutathione (GSH) content and the antioxidant enzymes
catalase, glutathione peroxidase (GPx), and glutathione reductase (GR), which reduced the oxidative stress
markers. Moreover, the improvement of antioxidant response by SFN restored S-glutathionylation in the mitochondrial
fraction. Activated Nrf2 also reduced inflammation by lessening the nucleotide-binding domain-like
receptor family pyrin domain containing 3 and interleukin 1β (IL-1β) production. Reducing oxidative stress and
inflammation prevented apoptosis by avoiding caspase 3 cleavage and increasing B-cell lymphoma 2 (Bcl2)
levels. Taken together, the obtained results in our study showed that the upregulation of Nrf2 by SFN decreases
oxidative stress, preventing inflammation and apoptosis cell death during the release of UUO.
... To enable formation of mitophagosomes in mitophagy, mitochondrial priming is regulated by both ubiquitin-dependent PINK1/Parkin pathway and ubiquitin-independent mitophagy receptors, including BNIP3/BNIP3L/FUNDC1 25 . It has been reported that PINK1, Parkin or BNIP3 deficiency exacerbates ischemic/reperfusion-, cisplatin-, contrast medium-, or sepsis-induced acute kidney injury (AKI) [39][40][41][42][43] , as well as unilateral ureter obstruction-induced CKD 44,45 . Concurring with the notion that mitophagy plays a protective role in proximal tubular cells under pathogenic conditions, our study further illuminates the important therapeutic implication of MANF as a mitophagy/autophagy activator in ADTKD-UMOD, which can also directly promote autophagic clearance of mutant UMOD. ...
Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD- UMOD ), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD- UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
... 256 In unilateral ureteral obstruction (UUO)-renal fibrosis, PINK1 or Parkin deficiency not only leads to insufficient mitophagy but also increases the production and damage of mitochondrial ROS in renal tubular cells after UUO, consequently aggravating renal fibrosis. 257 The mitophagy activator UMI-77 reduces profibrotic responses in renal tubular epithelial cells by activating mitophagy. 258 In addition, in the UUO-induced experiments, PINK1 or Parkin deletion led to excessive accumulation of abnormal mitochondria in macrophages, which accelerated the transformation of macrophages into profibrotic /M2 macrophages and the progression of renal fibrosis. ...
Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.
... Based on the findings described above, we hypothesized that increased mitochondrial dysfunction and mtROS production were responsible for the deterioration of kidney injury due to TRPM2 silencing. Mito-TEMPO was shown to be effective in reducing ischemic AKI (41) and renal fibrosis (42) through eliminating excessive mtROS. Therefore, we tested this hypothesis by determining the effects of pretreatment with Mito-TEMPO ( Figure 4A). ...
Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis. Methods: Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and Trpm2-knockout mice and primary cells. RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity. Results: Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin. Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger. TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca2+ influx and subsequent up-regulation of AKT-mTOR signaling. Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor. Conclusion: Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca2+-AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.
