Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17+/+ wild-type (WT) and Mpv17−/− knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00570.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. F520-F531 ◽

Cited By ~ 42

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.

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SIRT1 Alleviates Aldosterone-Induced Podocyte Injury by Suppressing Mitochondrial Dysfunction and NLRP3 Inflammasome Activation

Kidney Diseases ◽

10.1159/000513884 ◽

2021 ◽

pp. 1-13

Author(s):

Mingzhu Jiang ◽

Min Zhao ◽

Mi Bai ◽

Juan Lei ◽

Yanggang Yuan ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Knockout Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Glomerular Injury ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation

Background: Podocyte injury contributes to progressive glomerulosclerosis. Previously, we demonstrated the important role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mediating the podocyte injury induced by aldosterone. Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+-dependent deacetylase that is associated with the regulation of cellular inflammation. However, whether the activation of the NLRP3 inflammasome in podocytes is regulated by SIRT1, and the mechanism involved, remains unknown. Methods: In this study, we detected SIRT1 expression in patients with podocyte disease and performed an aldosterone infusion model in podocyte-specific Sirt1 knockout mice. In cultured podocytes, we used plasmids to overexpress SIRT1 and treated the podocyte with aldosterone. Results: SIRT1 was significantly decreased in the glomeruli of patients with podocyte disease. Sirt1-deficient mice showed significant urinary albumin excretion after aldosterone infusion, and the severity of the glomerular injury was significantly greater in podocyte-specific Sirt1 knockout mice than in the wild-type mice. Moreover, podocyte conditional Sirt1 knockout aggravated NLRP3 inflammasome activation and mitochondrial dysfunction (MtD). In vitro, overexpression of SIRT1 inhibited NLRP3 activation, protected against MtD and podocyte injury. Conclusion: Taken together, these findings revealed a novel regulatory mechanism of the NLRP3 inflammasome by SIRT1 by promoting mitochondrial function, which provides some potential targets for the treatment of glomerular diseases.

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

PPAR Research ◽

10.1155/2015/720383 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 7

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.

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

Cellular Physiology and Biochemistry ◽

10.1159/000430174 ◽

2015 ◽

Vol 36 (5) ◽

pp. 2072-2082 ◽

Cited By ~ 21

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.

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Ret is critical for podocyte survival following glomerular injury in vivo

AJP Renal Physiology ◽

10.1152/ajprenal.00483.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. F774-F783 ◽

Cited By ~ 2

Author(s):

Guoqing Hou ◽

Victoria Wu ◽

Gulmohar Singh ◽

Lawrence B. Holzman ◽

Cynthia C. Tsui

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Glomerular Injury ◽

Glomerular Diseases ◽

In Vivo Models ◽

Conditional Deletion ◽

Immune Mediated ◽

Kidney Morphogenesis

Podocyte injury and loss directly cause proteinuria and the progression to glomerulosclerosis. Elucidation of the mechanisms of podocyte survival and recovery from injury is critical for designing strategies to prevent the progression of glomerular diseases. Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated in both nonimmune and immune-mediated in vitro and in vivo models of glomerular diseases. We investigated whether Ret, a known receptor tyrosine kinase critical for kidney morphogenesis and neuronal growth and development, is necessary for glomerular and podocyte development and survival in vivo. Since deletions of both GDNF and Ret result in embryonic lethality due to kidney agenesis, we examined the role of Ret in vivo by generating mice with a conditional deletion of Ret in podocytes ( Ret flox/flox; Nphs2-Cre). In contrast to the lack of any developmental and maintenance deficits, Ret flox/flox; Nphs2-Cre mice showed a significantly enhanced susceptibility to adriamycin nephropathy, a rodent model of focal segmental glomerulosclerosis. Thus, these findings demonstrated that the Ret signaling pathway is important for podocyte survival and recovery from glomerular injury in vivo.

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p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction

AJP Renal Physiology ◽

10.1152/ajprenal.00055.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. F798-F808 ◽

Cited By ~ 19

Author(s):

Yanggang Yuan ◽

Aiqing Zhang ◽

Jia Qi ◽

Hui Wang ◽

Xi Liu ◽

...

Keyword(s):

Animal Model ◽

Mitochondrial Dysfunction ◽

Therapeutic Intervention ◽

Mitochondrial Fission ◽

Related Protein ◽

Glomerular Diseases ◽

Podocyte Injury ◽

P53 Expression

Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.

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Research on The Effect of Amyloid beta on Mitochondrial Dysfunction In vivo and In vitro*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2009.00556 ◽

2010 ◽

Vol 37 (2) ◽

pp. 154-160 ◽

Cited By ~ 1

Author(s):

Ling-Ling LIU ◽

Bai-Yang SHENG ◽

Kai GONG ◽

Nan-Ming ZHAO ◽

Xiu-Fang ZHANG ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Amyloid Beta

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Fe3O4@Pt nanoparticles to enable combinational electrodynamic/chemodynamic therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00957-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tong Chen ◽

Qiang Chu ◽

Mengyang Li ◽

Gaorong Han ◽

Xiang Li

Keyword(s):

Fenton Reaction ◽

Pt Nanoparticles ◽

Therapeutic Modality ◽

Ros Generation ◽

Tumor Treatment ◽

Superior Efficacy ◽

Platinum Nanocrystals ◽

First Time

AbstractElectrodynamic therapy (EDT) has recently emerged as a potential external field responsive approach for tumor treatment. While it presents a number of clear superiorities, EDT inherits the intrinsic challenges of current reactive oxygen species (ROS) based therapeutic treatments owing to the complex tumor microenvironment, including glutathione (GSH) overexpression, acidity and others. Herein for the first time, iron oxide nanoparticles are decorated using platinum nanocrystals (Fe3O4@Pt NPs) to integrate the current EDT with chemodynamic phenomenon and GSH depletion. Fe3O4@Pt NPs can effectively induce ROS generation based on the catalytic reaction on the surface of Pt nanoparticles triggered by electric field (E), and meanwhile it may catalyze intracellular H2O2 into ROS via Fenton reaction. In addition, Fe3+ ions released from Fe3O4@Pt NPs under the acidic condition in tumor cells consume GSH in a rapid fashion, inhibiting ROS clearance to enhance its antitumor efficacy. As a result, considerable in vitro and in vivo tumor inhibition phenomena are observed. This study has demonstrated an alternative concept of combinational therapeutic modality with superior efficacy.

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FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00542-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Dezhong Wang ◽

Yuan Yin ◽

Shuyi Wang ◽

Tianyang Zhao ◽

Fanghua Gong ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Metabolic Regulation ◽

Cardiac Injury ◽

Serum Levels ◽

Ros Generation ◽

Dependent Manner ◽

Cardiac Tissues ◽

Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

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

Cell & Bioscience ◽

10.1186/s13578-021-00563-y ◽

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.

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