scholarly journals Effects ofAstragalusPolysaccharides on Dysfunction of Mitochondrial Dynamics Induced by Oxidative Stress

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yan-Feng Huang ◽  
Lu Lu ◽  
Da-Jian Zhu ◽  
Ming Wang ◽  
Yi Yin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanism ◽  
Mitochondrial Dynamics ◽  
Chronic Fatigue ◽  
Excessive Exercise ◽  
Functional Changes

This paper studied the chronic fatigue induced by excessive exercise and the restoration effects ofAstragaluspolysaccharides (APS) on mitochondria. In vivo, we found that excessive exercise could cause oxidative stress statue which led to morphological and functional changes of mitochondria. The changes, including imbalance between mitochondria fusion-fission processes, activation of mitophagy, and decrease of PGC-1αexpression, could be restored by APS. We further confirmed in vitro, and what is more, we found that APS may ameliorate mitochondrial dysfunction through Sirt1 pathway. Based on the results, we may figure out part of the molecular mechanism of mitochondrial amelioration by APS.

scholarly journals Mfn2 Overexpression Attenuates MPTP Neurotoxicity In Vivo

2021 ◽  
Vol 22 (2) ◽  
pp. 601
Author(s):  
Fanpeng Zhao ◽  
Quillan Austria ◽  
Wenzhang Wang ◽  
Xiongwei Zhu
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Significant Loss ◽  
Critical Event ◽  
Mitochondrial Fragmentation ◽  
Wild Type Littermate ◽  
Littermate Control ◽  
Mptp Administration

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson’s disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

scholarly journals HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

2021 ◽  
Vol 14 ◽  
Author(s):  
Krystal English ◽  
Michelle Craig Barton
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Health Concern ◽  
Major Player ◽  
Class Iib ◽  
Voltage Gated Ion Channels

Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.

scholarly journals Daphnetin Attenuated Cisplatin-Induced Acute Nephrotoxicity With Enhancing Antitumor Activity of Cisplatin by Upregulating SIRT1/SIRT6-Nrf2 Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaoye Fan ◽  
Wei Wei ◽  
Jingbo Huang ◽  
Liping Peng ◽  
Xinxin Ci
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Cell Damage ◽  
Protective Effects ◽  
Normal Tissues ◽  
Nrf2 Signaling Pathway ◽  
Apoptosis Pathways ◽  
Underlying Mechanisms

Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.

The Association of Neuronal Stress with Activating Transcription Factor 3 in Dorsal Root Ganglion of in vivo and in vitro Models of Bortezomib- Induced Neuropathy

2018 ◽  
Vol 19 (1) ◽  
pp. 50-64 ◽  
Author(s):  
Yiting Yin ◽  
Xin Qi ◽  
Yuan Qiao ◽  
Huaxiang Liu ◽  
Zihan Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Cell Apoptosis ◽  
Activating Transcription Factor 3 ◽  
Drg Neurons ◽  
Activating Transcription Factor ◽  
Intracellular Oxidative Stress

Background: The notion that proteasome inhibitor bortezomib (BTZ) induced intracellular oxidative stress resulting in peripheral neuropathy has been generally accepted. The association of mitochondrial dysfunction, cell apoptosis, and endoplasmic reticulum (ER) stress with intracellular oxidative stress is ambiguous and still needs to be investigated. The activation of activating transcription factor 3 (ATF3) is a stress-hub gene which was upregulated in dorsal root ganglion (DRG) neurons after different kinds of peripheral nerve injuries. Objective: To investigate a mechanism underlying the action of BTZ-induced intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress via activation of ATF3. </P><P> Methods: Primary cultured DRG neurons with BTZ induced neurotoxicity and DRG from BTZ induced painful peripheral neuropathic rats were used to approach these questions. Results: BTZ administration caused the upregulation of ATF3 paralleled with intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress in DRG neurons both in vitro and in vivo. Blocking ATF3 signaling by small interfering RNA (siRNA) gene silencing technology resulted in decreased intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress in DRG neurons after BTZ treatment. This study exhibited important mechanistic insight into how BTZ induces neurotoxicity through the activation of ATF3 resulting in intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress and provided a novel potential therapeutic target by blocking ATF3 signaling.

Abstract 392: Angiotensin II TypeI Receptor-mediated Mitochondrial Fission and Suppression of Mitophagy Play Crucial Role in Vascular Senescence and Arteriosclerosis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Double Knockout ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Metabolic stress including oxidized low density lipoprotein (ox-LDL) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that undergo quality control by mitochondrial dynamics and mitophagy. This study aims to clarify whether and how mitochondrial dynamics and mitophagy are involved in the etiology of vascular senescence and arteriosclerosis. Methods: VSMC were stimulated by ox-LDL. We also conducted in vivo experiment using C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE mice and Angiotensin II Type1 Receptor (AT1R). Results: Treatment of ox-LDL forced mitochondria to fission through activation of Drp1, induced mitochondrial dysfunction and oxidative stress, and developed cellular senescence. Inhibition of either Drp1, AT1R, MAPK retarded them, suggesting that mitochondrial fission plays key roles to develop premature cellular senescence and is modulated by AT1R/MAPK signal.Administration of ox-LDL decreased the number of mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R signal inhibition increased mitophagy which was not affected by Atg7 knockdown, whereas it was decreased by either Rab9 or Ulk1 knockdown. Immunohistochemistry showed Rab9 dots were co-localized to TOMM20 and LAMP2, whereas LC3 dots were not, suggesting that AT1R signal induces mitophagy through Rab9-dependent alternative autophagy. The degree of vascular senescence was higher, the number of fused mitochondria and mitochondrial function were lower and mitochondrial oxidative stress was higher in ApoE KO than those in WT. DKO attenuated these adverse effect of ApoE KO. Conclusion: AT1R regulates vascular senescence and arteriosclerosis via induction of mitochondrial fission and inhibition of mitophagy.

scholarly journals Aldosterone Excess Induced Mitochondria Decrease and Dysfunction via Mineralocorticoid Receptor and Oxidative Stress In Vitro and In Vivo

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 946
Author(s):  
Cheng-Hsuan Tsai ◽  
Chien-Ting Pan ◽  
Yi-Yao Chang ◽  
Shih-Yuan Peng ◽  
Po-Chin Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Cardiac Mitochondria ◽  
Mice Model ◽  
Atp Production ◽  
And Oxidative Stress

Aldosterone excess plays a major role in the progression of cardiac dysfunction and remodeling in clinical diseases such as primary aldosteronism and heart failure. However, the effect of aldosterone excess on cardiac mitochondria is unclear. In this study, we investigated the effect of aldosterone excess on cardiac mitochondrial dysfunction and its mechanisms in vitro and in vivo. We used H9c2 cardiomyocytes to investigate the effect and mechanism of aldosterone excess on cardiac mitochondria, and further investigated them in an aldosterone-infused ICR mice model. The results of the cell study showed that aldosterone excess decreased mitochondrial DNA, COX IV and SOD2 protein expressions, and mitochondria ATP production. These effects were abolished or attenuated by treatment with a mineralocorticoid receptor (MR) antagonist and antioxidant. With regard to the signal transduction pathway, aldosterone suppressed cardiac mitochondria through an MR/MAPK/p38/reactive oxygen species pathway. In the mouse model, aldosterone infusion decreased the amount of cardiac mitochondrial DNA and COX IV protein, and the effects were also attenuated by treatment with an MR antagonist and antioxidant. In conclusion, aldosterone excess induced a decrease in mitochondria and mitochondrial dysfunction via MRs and oxidative stress in vitro and in vivo.

scholarly journals DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

2021 ◽  
Vol 22 (11) ◽  
pp. 5675
Author(s):  
Jinglong Chen ◽  
Danping Wang ◽  
Yibo Zong ◽  
Xiaojing Yang
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Liver Diseases ◽  
Antioxidant Effect ◽  
Cellular Damage ◽  
Autophagic Flux

Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H2O2-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H2O2 and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl4 and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy.

scholarly journals Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Thomas J. Krzystek ◽  
Rupkatha Banerjee ◽  
Layne Thurston ◽  
JianQiao Huang ◽  
Kelsey Swinter ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Dependent Manner ◽  
Shape Distribution ◽  
Mitochondrial Homeostasis ◽  
C Terminus

AbstractMitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson’s disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson’s disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1–120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1–120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1–120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.

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