PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury.
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ABSTRACT:
SUBMITTER: Yuan L
PROVIDER: S-EPMC8034953 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Renal tubular epithelial cells are one of the high energy-consuming cell types, which mainly depend on mitochondrial energy supply. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that is involved in alcohol metabolism and mitochondrial oxidative ATP production; however, its function in mitochondrial homoeostasis in acute kidney injury (AKI) is unclear. Here, we found that ALDH2 expression was predominantly decreased in cisplatin or maleic acid (MA) models both in vivo and in vitro. ALDH2 knockout (KO) mice exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after cisplatin injection. In contrast, ALDH2 activation alleviated AKI and tubular cell apoptosis in both cisplatin- and MA-induced models. RNA sequencing revealed that the oxidative phosphorylation pathway was positively enriched in the renal tissues after Alda-1 pre-treatment in MA-induced mice. ALDH2 activation restored mitochondrial structure, mitochondrial membrane potential, and respiration rate, but downregulated glycolysis in MA-induced mice and human renal proximal tubular epithelial (HK-2) cells. Mechanistically, co-immunoprecipitation assays revealed that ALDH2 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, and advanced its nuclear translocation. Subsequently, PGC-1α knockdown almost abolished the improvement of ALDH2 activation on MA-induced tubular epithelial cells damage. Thus, our study revealed that ALDH2 activation alleviated mitochondrial dysfunction in AKI by enhancing PGC-1α-mediated mitochondrial biogenesis. Hence, ALDH2 may act as a potential therapeutic target to prevent AKI progression.
| S-EPMC9860042 | biostudies-literature
Project description:Aims: Cisplatin, an anticancer drug, always leads to nephrotoxicity by causing mitochondrial dysfunction. As a major mechanism for cellular self-degradation, autophagy has been proven to protect against cisplatin-induced acute kidney injury (AKI). Based on the activation of autophagy induced by trehalose, we aimed to investigate the nephroprotective effects of trehalose on cisplatin-induced AKI and its underlying mechanisms. Results: Due to the activation of autophagy, mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species (ROS), and reduced ATP generation) and apoptosis induced by cisplatin were markedly inhibited in trehalose-treated HK2 cells in vitro. Based on the transcriptional regulation role of transcription factor EB (TFEB) in autophagy and lysosome, we characterized trehalose-induced nuclear translocation of TFEB. Furthermore, consistent with trehalose treatment, overexpression of TFEB inhibited cell injury induced by cisplatin. However, the protective effects of trehalose were largely abrogated in tfeb-knockdown cells. In vivo, cisplatin injection resulted in severe kidney dysfunction and histological damage in mice. Trehalose administration activated TFEB-mediated autophagy, alleviated mitochondrial dysfunction and kidney injury in AKI mice. Innovation and conclusion: Our data suggest that trehalose treatment preserves mitochondria function via activation of TFEB-mediated autophagy and attenuates cisplatin-induced kidney injury.
| S-EPMC7255003 | biostudies-literature
Project description:Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.
| S-EPMC9258713 | biostudies-literature
Project description:Cisplatin-induced acute kidney injury (CIAKI) is a common complication in patients receiving cisplatin-based chemotherapy. But the effective therapies for CIAKI are not available. Retinoic acid (RA), the main derivative of vitamin A, has the potential to reduce inflammation and fibrosis in renal injury. However, the effect and mechanism of RA on CIAKI are still unclear. The aim of this study is to investigate whether RA can alleviate CIAKI through activation of autophagy. In this study, we evaluated the effect of RA, RA's effect on autophagy and apoptosis after cisplatin-induced injury on renal tubular epithelial cells (RTECs) by LDH assay, immunoblotting and TUNEL staining. Then we established Atg5flox/flox:Cagg-Cre mice in which Cagg-Cre is tamoxifen inducible, and Atg5 is conditional deleted after tamoxifen injection. The effect of RA and RA's effect on autophagy on CIAKI model were evaluated by biochemical assessment, hematoxylin and eosin (HE) staining, and immunoblotting in the control and autophagy deficient mice. In vitro, RA protected RTECs against cisplatin-induced injury, activated autophagy, and inhibited cisplatin-induced apoptosis. In vivo, RA attenuated cisplatin-induced tubular damage, shown by improved renal function, decreased renal cast formation, decreased NGAL expression, and activated autophagy in the control mice. Furthermore, the nephrotoxicity of cisplatin was aggravated, and the protective effect of RA was attenuated in autophagy deficient mice, indicating that RA works in an autophagy-dependent manner on CIAKI. RA activates autophagy and alleviates CIAKI in vivo and in vitro.Thus RA may be a renoprotective adjuvant for cisplatin-based chemotherapy.
| S-EPMC7348052 | biostudies-literature
Project description:Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagy-lysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/calcineurin. At the later stages of ischemia, a gradual decrease in the level of nuclear TFEB was coupled with a progressive decline in lysosomal activity, accumulation of autophagosomes and autophagy substrates, and exacerbation of the ischemic injury. Notably, neuron-specific overexpression of TFEB significantly enhanced ALP function and rescued the ischemic damage, starting as early as 6 h and even lasting to 48 h after ischemia. Furthermore, neuron-specific knockdown of TFEB markedly reversed the activation of ALP and further aggravated the neurological deficits and ischemic outcome at the early stage of pMCAO. These results highlight neuronal-targeted TFEB as one of the key players in the pMCAO-mediated dysfunction of ALP and ischemic injury, and identify TFEB as a promising target for therapies aimed at neuroprotection in cerebral ischemia. Abbreviations: AAV, adeno-associated virus; AIF1/IBA1, allograft inflammatory factor 1; ALP, autophagy-lysosomal pathway; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; CsA, cyclosporin A; GFAP, glial fibrillary acidic protein; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated protein 1 light chain 3; MAP2, microtubule-associated protein 2; mNSS, modified Neurological Severity Score; MTOR, mechanistic target of rapamycin kinase; OGD, oxygen and glucose deprivation; pMCAO, permanent middle cerebral artery occlusion; RBFOX3/NeuN, RNA binding fox-1 homolog 3; SQSTM1, sequestosome1; TFEB, transcription factor EB; TTC, 2,3,5-triphenyltetrazolium chloride.
| S-EPMC6351122 | biostudies-literature
Project description:PurposeInvestigate the mechanism of how sodium butyrate (NaBut) improves mitochondrial function and kidney tissue injury in diabetic kidney disease (DKD) via the AMPK/PGC-1α pathway.MethodsAssess the effects of NaBut on glucose and insulin tolerance, urine, and gut microbial composition in db/db and db/m mice. Use flow cytometry and western blotting to detect the effects of NaBut on apoptosis, kidney mitochondrial function, and AMPK/PGC-1α signaling. Use HK-2 cells induced by high glucose (HG) to establish the DKD model in vitro and detect changes in the AMPK/PGC-1α signaling pathway and mitochondrial function after NaBut intervention.ResultsNaBut attenuated blood glucose levels and reversed increases in urine and serum levels of glucose, BUN, Ucr, TG, TC, and UAE in db/db mice. NaBut improved insulin tolerance, reversed PGC-1α and p-AMPK expression level in the kidneys of db/db mice, and improved lipid accumulation and mitochondrial function. NaBut was able to reverse the effects of elevated glucose, compound C, and siRNA-PGC on ROS and ATP levels. Additionally, it increased protein expression of PGC-1α and p-AMPK.ConclusionNaBut activates the kidney mitochondrial AMPK/PGC-1α signaling pathway and improves mitochondrial dysfunction in DKD, thus protecting kidney tissue in vitro and in vivo.
| S-EPMC11001342 | biostudies-literature
Project description:Data for p53 mutation in prostate cancer in The Cancer Genome Atlas database revealed that >85% of p53 mutations occurred in the p53 DNA binding domain. These mutations not only severely damage the function of the p53 protein, but also reduce the disease‑free survival of patients. Peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) is involved in the regulation of mitochondrial function and is highly expressed in prostate cancer PC3 and DU145 cells with p53 deletion or mutation. However, whether p53 negatively regulates PGC‑1α in prostate cancer cells remains to be elucidated. In the present study, p53 overexpression was induced in prostate cancer PC3 cells. Subsequently, the expression levels of PGC‑1α and alterations to mitochondrial function were assessed. Moreover, PGC‑1α was activated in prostate cancer PC3 cells using ZLN005 to investigate alterations to mitochondrial function and cell apoptosis. The present study revealed that p53 decreased the expression and nuclear localization of the PGC‑1α protein and induced mitochondrial dysfunction. Activation of PGC‑1α partially reversed p53‑mediated mitochondrial dysfunction. Inhibition of the p53/PGC‑1α pathway on mitochondrial biogenesis and fission‑/fusion‑associated gene and protein expression were associated with mitochondrial dysfunction. p53/PGC‑1α‑mediated mitochondrial dysfunction promoted apoptosis of PC3 prostate cancer cells. The results indicated that PGC‑1α is an essential target of p53‑induced apoptosis in prostate cancer cells and indicated that targeting PGC‑1α may provide a new therapeutic strategy for prostate cancer.
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Project description:Mitochondria take part in a network of intracellular processes that regulate homeostasis. Defects in mitochondrial function are key pathophysiological changes during AKI. Although Wnt/β-catenin signaling mediates mitochondrial dysfunction in chronic kidney fibrosis, little is known of the influence of β-catenin on mitochondrial function in AKI. To decipher this interaction, we generated an inducible mouse model of tubule-specific β-catenin overexpression (TubCat), and a model of tubule-specific β-catenin depletion (TubcatKO), and induced septic AKI in these mice with lipopolysaccharide (LPS) and aseptic AKI with bilateral ischemia-reperfusion. In both AKI models, tubular β-catenin stabilization in TubCat animals significantly reduced BUN/serum creatinine, tubular damage (NGAL-positive tubules), apoptosis (TUNEL-positive cells) and necroptosis (phosphorylation of MLKL and RIP3) through activating AKT phosphorylation and p53 suppression; enhanced mitochondrial biogenesis (increased PGC-1α and NRF1) and restored mitochondrial mass (increased TIM23) to re-establish mitochondrial homeostasis (increased fusion markers OPA1, MFN2, and decreased fission protein DRP1) through the FOXO3/PGC-1α signaling cascade. Conversely, kidney function loss and histological damage, tubular cell death, and mitochondrial dysfunction were all aggravated in TubCatKO mice. Mechanistically, β-catenin transfection maintained mitochondrial mass and activated PGC-1α via FOXO3 in LPS-exposed HK-2 cells. Collectively, these findings provide evidence that tubular β-catenin mitigates cell death and restores mitochondrial homeostasis in AKI through the common mechanisms associated with activation of AKT/p53 and FOXO3/PGC-1α signaling pathways.
| S-EPMC9768165 | biostudies-literature
Project description:AimsPreventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction.Main methodsRats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out.Key findingsMelatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves.SignificanceActivation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.
| S-EPMC7567935 | biostudies-literature
Project description:Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease.
| S-EPMC9025854 | biostudies-literature