scholarly journals AMPK, Mitochondrial Function, and Cardiovascular Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 4987 ◽  
Author(s):  
Shengnan Wu ◽  
Ming-Hui Zou
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cellular Response ◽  
Adenosine Monophosphate ◽  
Therapeutic Effects ◽  
Ampk Signaling ◽  
Mitochondrial Homeostasis ◽  
Redox Sensor ◽  
Intracellular Energy ◽  
The Impact

Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.

scholarly journals HuoXue QianYang QuTan Recipe attenuates left ventricular hypertrophy in obese hypertensive rats by improving mitochondrial function through SIRT1/PGC-1α deacetylation pathway

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Jing Wang ◽  
Zhen-Hua Dong ◽  
Ming-Tai Gui ◽  
Lei Yao ◽  
Jian-Hua Li ◽  
...  
Keyword(s):  
Body Weight ◽  
Left Ventricular Hypertrophy ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ventricular Hypertrophy ◽  
Vital Role ◽  
Left Ventricular ◽  
Therapeutic Effects ◽  
Glycolipid Metabolism ◽  
Obesity Hypertension

Abstract Mitochondrial dysfunction plays a vital role in the progression of left ventricular hypertrophy (LVH). Previous studies have confirmed that the disorder of SIRT1/PGC-1α deacetylation pathway aggravated mitochondrial dysfunction. HuoXue QianYang QuTan Recipe (HQQR) is a commonly used prescription that has shown therapeutic effects on obesity hypertension and its complications. However, the potential mechanisms are still unclear. In the present study, obesity hypertension (OBH) was established in rats and we investigated the efficacy and mechanisms of HQQR on LVH. Rats were divided into the five groups: (1) WKY-ND group, (2) SHR-ND group, (3) OBH-HF group, (4) OBH-HF/V group and (5) OBH-HF/H group. We evaluated body weight, Lee index and blood pressure (BP) before and every 2 weeks after treatment. After 10 weeks of treatment, we mainly detected glycolipid metabolic index, the severity of LVH, mitochondrial function along with SIRT1/PGC-1α deacetylation pathway. Our results showed that HQQR significantly lowered body weight, Lee index, BP and improved the disorder of glycolipid metabolism in OBH rats. Importantly, we uncovered HQQR could alleviate mitochondrial dysfunction in OBH rats by regulating SIRT1/PGC-1α deacetylation pathway. These changes could be associated with the inhibition of LVH.

scholarly journals Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells

2020 ◽  
Author(s):  
Luca Peruzzotti-Jametti ◽  
Joshua D. Bernstock ◽  
Giulia Manferrari ◽  
Rebecca Rogall ◽  
Erika Fernandez-Vizarra ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Extracellular Vesicles ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mononuclear Phagocytes ◽  
Host Cells ◽  
Target Cells ◽  
Therapeutic Effects

AbstractNeural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs).EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics.Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells.Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs (Mito-EVs) with conserved membrane potential and respiration. We found that the transfer of Mito-EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of Mito-EVs into inflammatory professional phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits.Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via Mito-EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

Berberine on the Prevention and Management of Cardiometabolic Disease: Clinical Applications and Mechanisms of Action

2021 ◽  
pp. 1-22
Author(s):  
Richard Y. Cao ◽  
Yuntao Zheng ◽  
Ying Zhang ◽  
Lingling Jiang ◽  
Qing Li ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Biological Activities ◽  
Heart Diseases ◽  
Wide Spectrum ◽  
Adenosine Monophosphate ◽  
Ionic Channels ◽  
Cardiometabolic Disease ◽  
Therapeutic Effects ◽  
Ampk Signaling ◽  
Traditional Chinese Herbal Medicine

Berberine is an alkaloid from several medicinal plants originally used to treat diarrhea and dysentery as a traditional Chinese herbal medicine. In recent years, berberine has been discovered to exhibit a wide spectrum of biological activities in the treatment of diverse diseases ranging from cancer and neurological dysfunctions to metabolic disorders and heart diseases. This review article summarizes the clinical practice and laboratory exploration of berberine for the treatment of cardiometabolic and heart diseases, with a focus on the novel insights and recent advances of the underlying mechanisms recognized in the past decade. Berberine was found to display pleiotropic therapeutic effects against dyslipidemia, hyperglycemia, hypertension, arrhythmia, and heart failure. The mechanisms of berberine for the treatment of cardiometabolic disease involve combating inflammation and oxidative stress such as inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9) activation, regulating electrical signals and ionic channels such as targeting human ether-a-go-go related gene (hERG) currents, promoting energy metabolism such as activating adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, modifying gut microbiota to promote transforming of berberine into its intestine-absorbable form, and interacting with non-coding RNAs via targeting multiple signaling pathways such as AMPK, mechanistic target of rapamycin (mTOR), etc. Collectively, berberine appears to be safe and well-tolerated in clinical practice, especially for those who are intolerant to statins. Knowledge from this field may pave the way for future development of more effective pharmaceutical approaches for managing cardiometabolic risk factors and preventing heart diseases.

scholarly journals Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

2021 ◽  
Author(s):  
Amy L. Ball ◽  
Katarzyna M. Bloch ◽  
Lucille Rainbow ◽  
Xuan Liu ◽  
John Kenny ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Healthy Volunteers ◽  
Adverse Drug Reactions ◽  
Mitochondrial Function ◽  
Flux Analysis ◽  
Drug Reactions ◽  
Drug Induced ◽  
Mtdna Variation ◽  
Mitochondrial Genotype ◽  
The Impact

AbstractMitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

scholarly journals Rooibos Flavonoids, Aspalathin, Isoorientin, and Orientin Ameliorate Antimycin A-Induced Mitochondrial Dysfunction by Improving Mitochondrial Bioenergetics in Cultured Skeletal Muscle Cells

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6289
Author(s):  
Sinenhlanhla X. H. Mthembu ◽  
Christo J. F. Muller ◽  
Phiwayinkosi V. Dludla ◽  
Evelyn Madoroba ◽  
Abidemi P. Kappo ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
C2c12 Myotubes ◽  
Antimycin A ◽  
Mrna Levels ◽  
Expression Of Genes ◽  
Rooibos Tea ◽  
The Impact ◽  
Dietary Flavonoids

The current study investigated the physiological effects of flavonoids found in daily consumed rooibos tea, aspalathin, isoorientin, and orientin on improving processes involved in mitochondrial function in C2C12 myotubes. To achieve this, C2C12 myotubes were exposed to a mitochondrial channel blocker, antimycin A (6.25 µM), for 12 h to induce mitochondrial dysfunction. Thereafter, cells were treated with aspalathin, isoorientin, and orientin (10 µM) for 4 h, while metformin (1 µM) and insulin (1 µM) were used as comparators. Relevant bioassays and real-time PCR were conducted to assess the impact of treatment compounds on some markers of mitochondrial function. Our results showed that antimycin A induced alterations in the mitochondrial respiration process and mRNA levels of genes involved in energy production. In fact, aspalathin, isoorientin, and orientin reversed such effects leading to the reduced production of intracellular reactive oxygen species. These flavonoids further enhanced the expression of genes involved in mitochondrial function, such as Ucp 2, Complex 1/3, Sirt 1, Nrf 1, and Tfam. Overall, the current study showed that dietary flavonoids, aspalathin, isoorientin, and orientin, have the potential to be as effective as established pharmacological drugs such as metformin and insulin in protecting against mitochondrial dysfunction in a preclinical setting; however, such information should be confirmed in well-established in vivo disease models.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

scholarly journals Mesenchymal Stem Cells Ameliorate Mitochondrial Dysfunction in α - cells and Hyperglucagonemia in type 2 Diabetes via SIRT1/FoxO3a Signaling

2021 ◽  
Author(s):  
Jia Song ◽  
Lingshu Wang ◽  
Xinghong Guo ◽  
Qin He ◽  
Chen Cui ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Glucagon Secretion ◽  
Sirtuin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Umbilical Cord ◽  
Therapeutic Effects

Abstract Background: Dysregulation of α-cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stem cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α- cell mitochondrial dysfunction remains unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSCs (hucMSCs) on α-cell mitochondrial function and glucagon secretion in T2DM.Methods: hucMSCs were used to treat two kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α-cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by western blotting analysis.Results: In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued islet structure and decreased α- to β-cell ratio. Consistently, glucagon secretion from αTC1-6 cells was inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion.Conclusions: Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α-cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.

scholarly journals Electroconvulsive seizures induce autophagy by activating the AMPK signaling pathway in the rat frontal cortex

2019 ◽  
Author(s):  
Se Hyun Kim ◽  
Hyun Sook Yu ◽  
Soyoung Park ◽  
Hong Geun Park ◽  
Yong Min Ahn ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Therapeutic Effects ◽  
Ampk Signaling ◽  
Protein Levels ◽  
Compound C ◽  
Generalized Seizures ◽  
Rat Frontal Cortex

Abstract Background It is uncertain how electroconvulsive therapy (ECT)-induced generalized seizures exert their potent therapeutic effects on various neuropsychiatric disorders. Adenosine monophosphate-activated protein kinase (AMPK) plays a major role in maintaining metabolic homeostasis, and activates autophagic processes via unc-51-like kinase (ULK1). Evidence supports the involvement of autophagy system in the action mechanisms of antidepressants and antipsychotics. The effect of ECT on autophagy-related signaling requires further clarification. Methods The effect of electroconvulsive seizure (ECS) on autophagy, and its association with the AMPK signaling pathway, were investigated in the rat frontal cortex. ECS was provided once per day for 10 days (E10X), and compound C or 3-methyadenine was administered through an intracerebroventricular (i.c.v.) cannula. Molecular changes were analyzed with immunoblot, immunohistochemistry, and transmission electron microscopy (TEM) analyses. Results E10X increased p-Thr172-AMPKα immunoreactivity in rat frontal cortex neurons. E10X increased phosphorylation of upstream effectors of AMPK, such as LKB1, CaMKK, and TAK1, and of its substrates, ACC, HMGR, and GABABR2. E10X also increased p-Ser317-ULK1 immunoreactivity. At the same time, LC3-II and ATG5–ATG12 conjugate immunoreactivity increased, indicating activation of autophagy. An i.c.v injection of the AMPK inhibitor compound C attenuated the ECS-induced increase in ULK1 phosphorylation, as well as the protein levels of LC3-II and Atg5–Atg12 conjugate. TEM clearly showed an increased number of autophagosomes in the rat frontal cortex after E10X, which was reduced by i.c.v treatment with the autophagy inhibitor 3-methyadenine and compound C. Conclusions Repeated ECS treatments activated in vivo autophagy in the rat frontal cortex through the AMPK signaling pathway.

scholarly journals Neural stem cells traffic functional mitochondria via extracellular vesicles

PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001166
Author(s):  
Luca Peruzzotti-Jametti ◽  
Joshua D. Bernstock ◽  
Cory M. Willis ◽  
Giulia Manferrari ◽  
Rebecca Rogall ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Extracellular Vesicles ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mononuclear Phagocytes ◽  
Host Cells ◽  
Target Cells ◽  
Therapeutic Effects

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

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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