scholarly journals Huaier Cream Protects against Adriamycin-Induced Nephropathy by Restoring Mitochondrial Function via PGC-1αUpregulation

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Ruochen Che ◽  
Chunhua Zhu ◽  
Guixia Ding ◽  
Min Zhao ◽  
Mi Bai ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cell Injury ◽  
Therapeutic Drug ◽  
Mtdna Copy Number ◽  
Glomerular Diseases ◽  
Mitochondrial Transcription Factor ◽  
Transmission Electron

The mechanism by which Huaier, a Chinese traditional medicine, protects podocytes remains unclear. We designed the present study to examine whether mitochondrial function restored by PGC-1αserves as the major target of Huaier cream in protecting ADR nephropathy. After ADR administration, the podocytes exhibited remarkable cell injury and mitochondrial dysfunction. Additionally, ADR also reduced PGC-1αbothin vivoandin vitro. Following the Huaier treatment, the notable downregulation of PGC-1αand its downstream molecule mitochondrial transcription factor A (TFAM) were almost entirely blocked. Correspondingly, Huaier markedly ameliorated ADR-induced podocyte injury and mitochondrial dysfunction in both rat kidneys and incubated cells as it inhibited the decrease of nephrin and podocin expression, mtDNA copy number, MMP, and ATP content. Transmission electron microscopy result also showed that Huaier protected mitochondria against ADR-induced severe mitophagy and abnormal changes of ultrastructural morphology. In conclusion, Huaier can protect podocytes against ADR-induced cytotoxicity possibly by reversing the dysfunction of mitochondria via PGC-1αoverexpression, which may be a novel therapeutic drug target in glomerular diseases.

Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury

2013 ◽  
Vol 305 (4) ◽  
pp. F520-F531 ◽  
Author(s):  
Min Su ◽  
Asish-Roopchand Dhoopun ◽  
Yanggang Yuan ◽  
Songming Huang ◽  
Chunhua Zhu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Event ◽  
Mtdna Copy Number ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Atp Production ◽  
Podocyte Damage ◽  
Mitochondrial Transcription Factor

We previously showed that mitochondrial dysfunction (MtD) is involved in an aldosterone (Aldo)-induced podocyte injury. Here, the potential role of MtD in the initiation of podocyte damage was investigated. We detected the dynamic changes of urinary protein, urinary F2-isoprostane and renal malondialdehyde levels, kidney ultrastructure morphology, mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (ΔΨm), and nephrin and podocin expressions in Aldo-infused mice. Aldo infusion first induced renal oxidative stress, as evidenced by increased levels of urinary F2-isoprostane and renal malondialdehyde, and MtD, as demonstrated by reduced mtDNA, ΔΨm, and ATP production. Later, at 5 days after Aldo infusion, proteinuria and podocyte injury began to appear. In cultured podocytes, Aldo or hydrogen peroxide (H2O2) induced MtD after 2–8 h of treatment, whereas the podocyte damage, as shown by decreased nephrin and podocin expressions, occurred later after 12 h of treatment. Thus Aldo treatment both in vitro and in vivo indicated that MtD occurred before podocyte damage. Additionally, MtDNA depletion by ethidium bromide or mitochondrial transcription factor A (TFAM) RNAi induced MtD, further promoting podocyte damage. TFAM expression was found to be reduced in Aldo-infused mice and Aldo-treated podocytes. Adenoviral vector-mediated overexpression of TFAM prevented Aldo-induced MtD and protected against podocyte injury. Together, these findings support MtD as an early event in podocyte injury, and manipulation of TFAM may be a novel strategy for treatment of glomerular diseases such as podocytopathy.

scholarly journals ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tao Liang ◽  
Weijian Hang ◽  
Jiehui Chen ◽  
Yue Wu ◽  
Bin Wen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Calcium Transport ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

199 EVIDENCE FOR A NOVEL PERTURBATION IN CLONED FETUSES: MITOCHONDRIAL DNA DEPLETION

2007 ◽  
Vol 19 (1) ◽  
pp. 216
Author(s):  
S. Hiendleder ◽  
D. Bebbere ◽  
S. E. Ulbrich ◽  
V. Zakhartchenko ◽  
M. Weppert ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Real Time ◽  
Nuclear Gene ◽  
Complement C3 ◽  
Mtdna Copy Number ◽  
Vitro Fertilization ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Dna Depletion

The reported mtDNA turnover and plasticity of mtDNA copy number in mammalian zygotes and early embryos (McConnel and Petrie 2004 Reprod. Biomed. Online 9, 418–424) have revealed a potential for adverse effects of in vitro embryo techniques on mtDNA and mitochondrial function. We explored the effects of in vitro fertilization (IVF) and somatic cell nuclear transfer cloning (NT) on relative mtDNA amount and phenotype in viable bovine fetuses recovered 80 days after the initiation of embryonic development (Hiendleder et al. 2004 Biol. Reprod. 71, 217–223). We sampled brain, liver, and skeletal muscle to represent all 3 embryonic germ layers, and compared IVF-fetuses (n = 24), NT-fetuses (n = 23), and fetuses generated by in vivo insemination (controls, n = 24). This experimental approach allowed us to distinguish abnormalities specific to cloning from more general consequences of in vitro embryo manipulation. We analyzed relative mtDNA amounts by real-time quantitative PCR (qPCR) and amplified a segment of the mtDNA control region that was normalized against the nuclear gene complement C3. ANOVA (SPSS 13.0) of qPCR data and phenotypic parameters revealed significant effects of fetus group on mtDNA amount in liver (P < 0.05) and muscle (P < 0.01), and on fetus (P < 0.001), heart (P < 0.001), and liver (P < 0.001) weights. The mtDNA amount in all tissues from IVF-fetuses was normal, but mtDNA levels in liver (-23%; P < 0.05) and muscle (-24%; P < 0.01) of NT-fetuses were significantly lower than in controls. Fetuses derived from IVF- or NT-embryos were similar in weight and displayed fetal overgrowth (+19% and +22%; P < 0.001), but only the NT-fetuses were affected by disproportionate hepatomegaly and cardiomegaly with 31% and 49% increases (ANCOVA; P < 0.001) in their respective organ weights. This further partitioned NT-fetuses from IVF-fetuses and identified symptoms that are also encountered in mitochondrial DNA depletion syndromes (MDDS): a phenotypically heterogeneous group of human disorders characterized by loss of mtDNA from various tissues during development and associated respiratory chain dysfunction. The MDDS phenotypes have mainly been classified into a hepatocerebral (MIM 251880) or myopathic (MIM 609560) form, and neonates and infants display a spectrum of abnormalities, including hepatomegaly and cardiomegaly, that are similar or identical to phenotypic abnormalities commonly encountered in cloned mammals. Reduced mtDNA amounts in NT-fetuses could stem from perturbation of mtDNA during the reported turnover period, or be a secondary effect of epigenetic change in nuclear-encoded genes involved in mtDNA replication and stability. Mitochondrial transcription factor A (TFAM) is regulated by CpG methylation in vitro, but our real-time RT-PCR quantification of TFAM transcript in liver and muscle of a subset of NT- and control fetuses failed to detect significant differences (P > 0.10). In conclusion, our observed reduction of mtDNA amount in cloned fetuses provides the molecular basis for a mitochondrial perspective on pathological phenotypes of cloned mammals, and may explain similarities to mitochondrial disease in human.

scholarly journals MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function

2017 ◽  
Vol 29 (2) ◽  
pp. 449-461 ◽  
Author(s):  
Yan Guo ◽  
Jiajia Ni ◽  
Shuang Chen ◽  
Mi Bai ◽  
Jiajuan Lin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cell Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Pathogenic Role ◽  
Novel Target

Mitochondrial dysfunction has important roles in the pathogenesis of AKI, yet therapeutic approaches to improve mitochondrial function remain limited. In this study, we investigated the pathogenic role of microRNA-709 (miR-709) in mediating mitochondrial impairment and tubular cell death in AKI. In a cisplatin-induced AKI mouse model and in biopsy samples of human AKI kidney tissue, miR-709 was significantly upregulated in the proximal tubular cells (PTCs). The expression of miR-709 in the renal PTCs of patients with AKI correlated with the severity of kidney injury. In cultured mouse PTCs, overexpression of miR-709 markedly induced mitochondrial dysfunction and cell apoptosis, and inhibition of miR-709 ameliorated cisplatin-induced mitochondrial dysfunction and cell injury. Further analyses showed that mitochondrial transcriptional factor A (TFAM) is a target gene of miR-709, and genetic restoration of TFAM attenuated mitochondrial dysfunction and cell injury induced by cisplatin or miR-709 overexpression in vitro. Moreover, antagonizing miR-709 with an miR-709 antagomir dramatically attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. Collectively, our results suggest that miR-709 has an important role in mediating cisplatin-induced AKI via negative regulation of TFAM and subsequent mitochondrial dysfunction. These findings reveal a pathogenic role of miR-709 in acute tubular injury and suggest a novel target for the treatment of AKI.

scholarly journals Diabetes aggravates renal ischemia-reperfusion injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy

2019 ◽  
Vol 317 (4) ◽  
pp. F852-F864 ◽  
Author(s):  
Yuan-Yuan Yang ◽  
Dao-Jing Gong ◽  
Jian-Jian Zhang ◽  
Xiu-Heng Liu ◽  
Lei Wang
Keyword(s):  
Electron Microscopy ◽  
Mitochondrial Function ◽  
High Glucose ◽  
Mitochondrial Membrane ◽  
Ischemia Reperfusion ◽  
Oxygen Species ◽  
Transmission Electron ◽  
Normal Glucose

Diabetes could aggravate ischemia-reperfusion (I/R) injury, but the underlying mechanism is unclear. In the present study, we aimed to investigate whether diabetes exacerbates renal I/R injury and its possible mechanism. In vitro, HK-2 cells under normal or high glucose conditions were subjected to hypoxia (12 h) followed by reoxygenation (3 h) (H/R). Cell viability, intracellular ATP content, mitochondrial membrane potential, reactive oxygen species production, and apoptosis were measured. In vivo, streptozotocin-induced diabetic and nondiabetic rats were subjected to I/R. Renal pathology, function, and apoptosis were evaluated by hematoxylin and eosin staining, transmission electron microscopy, and Western blot analysis. Compared with the normal glucose + H/R group, mitochondrial function (ATP, mitochondrial membrane potential, and reactive oxygen species) and mitophagy were reduced in the high glucose + H/R group, as was expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and Parkin. Also, cells in the high glucose + H/R group exhibited more apoptosis compared with the normal glucose + H/R group, as assessed by flow cytometry, TUNEL staining, and Western blot analysis. Compared with normal rats that underwent I/R, diabetic rats that underwent I/R exhibited more severe tubular damage and renal dysfunction as well as expression of the apoptotic protein caspase-3. Meanwhile, diabetes alleviated mitophagy-associated protein expression in rats subjected to I/R, including expression of PINK1 and Parkin. Transmission electron microscopy indicated that the mitophagosome could be hardly observed and that mitochondrial morphology and structure were obviously damaged in the diabetes + I/R group. In conclusion, our results, for the first time, indicate that diabetes could aggravate I/R injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy in vivo and in vitro.

scholarly journals The Role of Mitochondria in Oocyte Maturation

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2484
Author(s):  
Anastasia Kirillova ◽  
Johan E. J. Smitz ◽  
Gennady T. Sukhikh ◽  
Ilya Mazunin
Keyword(s):  
Oocyte Maturation ◽  
Mitochondrial Function ◽  
Animal Cell ◽  
Mitochondrial Morphology ◽  
Mtdna Copy Number ◽  
Cell Organelles ◽  
Developmental Potential ◽  
The Right

With the nucleus as an exception, mitochondria are the only animal cell organelles containing their own genetic information, called mitochondrial DNA (mtDNA). During oocyte maturation, the mtDNA copy number dramatically increases and the distribution of mitochondria changes significantly. As oocyte maturation requires a large amount of ATP for continuous transcription and translation, the availability of the right number of functional mitochondria is crucial. There is a correlation between the quality of oocytes and both the amount of mtDNA and the amount of ATP. Suboptimal conditions of in vitro maturation (IVM) might lead to changes in the mitochondrial morphology as well as alternations in the expression of genes encoding proteins associated with mitochondrial function. Dysfunctional mitochondria have a lower ability to counteract reactive oxygen species (ROS) production which leads to oxidative stress. The mitochondrial function might be improved with the application of antioxidants and significant expectations are laid on the development of new IVM systems supplemented with mitochondria-targeted reagents. Different types of antioxidants have been tested already on animal models and human rescue IVM oocytes, showing promising results. This review focuses on the recent observations on oocytes’ intracellular mitochondrial distribution and on mitochondrial genomes during their maturation, both in vivo and in vitro. Recent mitochondrial supplementation studies, aiming to improve oocyte developmental potential, are summarized.

scholarly journals Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Wen-Jing Chen ◽  
Yan Cheng ◽  
Wen Li ◽  
Xiao-Kang Dong ◽  
Jian-liang Wei ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Effect ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mrna Level ◽  
Hypertensive Heart Disease ◽  
Ang Ii ◽  
Parp 1

Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.

IN VIVO POTENCY OF HEPARIN AND HEPARINOIDS TO INHIBIT RAT SMOOTH MUSCLE CELL PROLIFERATION

1987 ◽  
Author(s):  
Maciej Dryjski ◽  
Eileen Mikat ◽  
Thorir D Bjornsson
Keyword(s):  
Smooth Muscle ◽  
Endothelial Cell ◽  
Cell Injury ◽  
Response Curves ◽  
Endothelial Cell Injury ◽  
Antiproliferative Effects ◽  
Transmission Electron ◽  
Isolated Segment

The final response of endothelial cell injury in the arterial wall is characterized by proliferation of smooth muscle cells (SMC) in the intima to form a fibro-musculo-elastic plaque. Recent in vivo and in vitro studies have shown that heparin can inhibit proliferation of SMC. These studies, however, have not elucidated the relationships between heparin dose or concentration and its in vivo antiproliferative response. In the present study, we investigated the potency of standard heparin (SH), low molecular weight heparin (LMWH) and a mixture of sulfated glycosaminoglycans (Organon 10172) with respect to the in vivo inhibition of SMC proliferation after endothelial cell injury. The injury was achieved by a short infusion of air into an isolated segment of the rat carotid artery. The drugs were administered by the AlzetR miniosmotic pumps for two weeks, at which time the animals were sacrificed and both carotid arteries were fixed in situ for light and transmission electron microscopy. The index of the intimal SMC proliferation was the maximum intima to media area (I/M) ratio. The control animals developed a marked intimal thickening (I/M: 0.97). The animals treated with 50 units/kg/hr of SH exhibited significantly less intimal hyperplasia (I/M: 0.10). With decreasing SH doses, there were increases in the I/M ratio (5 units/kg/hr, I/M: 0.44; 0.5 units/kg/hr, I/M: 0.75, and 0.05 units/kg/hr, I/M: 0.84). LMWH in doses of 50 units/kg/hr inhibited SMC proliferation as effectively as SH (I/M: 0.10), however, at doses of 15 units/kg/hr the I/M ratio was 0.55. The effect of Organon 10172 was significant at doses of 50 units/kg/hr (I/M: 0.04), but limited at doses of 15 units/kg/hr (I/M: 0.61). The APTT and anti-Xa levels were only slightly increased in the animals treated with 50 units/kg/hr of LMWH and Organon 10172, but unchanged in the animals receiving SH and the lower doses of LMWH and Organon 10172. It is concluded that SH, LMWH and Organon 10172 have significant antiproliferative effects upon SMC. The differences in the dose-response curves suggests more than one mechanism of action.

scholarly journals TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

2015 ◽  
Vol 36 (5) ◽  
pp. 2072-2082 ◽  
Author(s):  
Peng Zhang ◽  
Yong Lu ◽  
Dong Yu ◽  
Dadong Zhang ◽  
Wei Hu
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Complex Activity ◽  
Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

scholarly journals Chronic Cadmium Exposure Impairs Macrophage Mitochondrial Homeostasis and Promotes Macrophage Polarization Contributing to Atherosclerosis via Regulating RIPK3 Signaling

2021 ◽  
Author(s):  
Jiexin Zhang ◽  
Weijing Feng ◽  
Peier Chen ◽  
Xiaodong Ning ◽  
Caiwen Ou ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Macrophage Polarization ◽  
Mitochondrial Fission ◽  
Inflammatory Factors ◽  
Mitochondrial Homeostasis ◽  
Cd Exposure ◽  
M1 Type

Abstract Background: Chronic cadmium (Cd) exposure can contribute to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. Here, we aimed to investigate the Cd-induced AS through macrophage polarization and tried to find out the mechanism of mitochondrial dysfunction caused by Cd exposure. Methods and results: In vitro, flow cytometry showed that Cd exposure markedly promoted M1-type polarization of macrophages, manifesting as the increasing expression of NF-kB, NLRP3 and their downstream inflammatory factors, IL-1β and IL-6. Mitochondrial function test revealed that the decreasing mitochondrial membrane potential and increasing superoxide (mROS) and mitochondrial fission were involved in Cd-induced macrophage polarization. Transmission electron microscope observation and immunofluorescence both identified the decrease of mitophage after Cd exposure. And improving mitochondrial function above significantly restored the balance of macrophage polarization. In vivo, Cd exposure was positively correlated with blood Cd concentration, and oil red O staining showed higher blood Cd significantly increased the area of AS plaques. Besides, M1-type polarization of macrophages and mitochondrial dysfunction were observed in mouse aortic roots through immunofluorescence and western blot as the dosage of Cd increasing. And the administered NAC or Mdivi-1, which decreased mROS or mitochondrial fission, markedly attenuated AS plaques and macrophage M1-type polarization in Cd-treated group. Finally, the up-regulated expressions of RIPK3 and p-MLKL were observed both in vitro and in vivo. And knocking out RIPK3 with decreasing expression of p-MLKL followed did improve mitochondrial dysfunction caused by Cd which effectively reversed macrophage polarization. Conclusion: Cd exposure activated RIPK3 pathway and impaired mitochondrial homeostasis, resulting in macrophage polarization to a pro-inflammatory phenotype and subsequent AS. These findings suggest that improving mitochondrial homeostasis may provide a potential therapeutic target for AS induced by chronic Cd exposure.

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