scholarly journals Interaction of α-synuclein and Parkin in iron toxicity on SH-SY5Y cells: implications in the pathogenesis of Parkinson's disease

2020 ◽  
Vol 477 (6) ◽  
pp. 1109-1122 ◽  
Author(s):  
Upasana Ganguly ◽  
Anindita Banerjee ◽  
Sankha Shubhra Chakrabarti ◽  
Upinder Kaur ◽  
Oishimaya Sen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Cell Viability ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Knock Down ◽  
Familial Type

The toxicity of accumulated α-synuclein plays a key role in the neurodegeneration of Parkinson's disease (PD). This study has demonstrated that iron in varying concentrations (up to 400 µM) causes an increase in α-synuclein content in SH-SY5Y cells associated with mitochondrial depolarization, decreased cellular ATP content and loss of cell viability during incubation up to 96 h. Knocking-down α-synuclein expression prevents cytotoxic actions of iron, which can also be prevented by cyclosporine A (a blocker of mitochondrial permeability transition pore). These results indicate that iron cytotoxicity is mediated by α-synuclein acting on mitochondria. Likewise siRNA mediated knock-down of Parkin causes an accumulation of α-synuclein accompanied by mitochondrial dysfunction and cell death during 48 h incubation under basal conditions, but these changes are not further aggravated by co-incubation with iron (400 µM). We have also analyzed mitochondrial dysfunction and cell viability in SH-SY5Y cells under double knock-down (α-synuclein and Parkin concurrently) conditions during incubation for 48 h with or without iron. Our results tend to suggest that iron inactivates Parkin in SH-SY5Y cells and thereby inhibits the proteasomal degradation of α-synuclein, and the accumulated α-synuclein causes mitochondrial dysfunction and cell death. These results have implications in the pathogenesis of sporadic PD and also familial type with Parkin mutations.

Mitochondrial dysfunction in Parkinson's disease

1999 ◽  
Vol 66 ◽  
pp. 85-97 ◽  
Author(s):  
J.Timothy Greenamyre ◽  
Gillian MacKenzie ◽  
Tsung-I Peng ◽  
Stacy E. Stephans
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nmda Receptor ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Time Course ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Receptor Activation ◽  
Mitochondrial Impairment

The cause of Parkinson's disease (PD) is unknown, but reduced activity of complex I of the electron-transport chain has been implicated in the pathogenesis of both mitochondrial permeability transition pore-induced Parkinsonism and idiopathic PD. We developed a novel model of PD in which chronic, systemic infusion of rotenone, a complex-I inhibitor, selectively kills dopaminergic nerve terminals and causes retrograde degeneration of substantia nigra neurons over a period of months. The distribution of dopaminergic pathology replicates that seen in PD, and the slow time course of neurodegeneration mimics PD more accurately than current models. Our model should enhance our understanding of neurodegeneration in PD. Metabolic impairment depletes ATP, depresses Na+/K(+)-ATPase activity, and causes graded neuronal depolarization. This relieves the voltage-dependent Mg2+ block of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor, which is highly permeable to Ca2+. Consequently, innocuous levels of glutamate become lethal via secondary excitotoxicity. Mitochondrial impairment also disrupts cellular Ca2+ homoeostasis. Moreover, the facilitation of NMDA-receptor function leads to further mitochondrial dysfunction. To a large part, this occurs because Ca2+ entering neurons through NMDA receptors has 'privileged' access to mitochondria, where it causes free-radical production and mitochondrial depolarization. Thus there may be a feed-forward cycle wherein mitochondrial dysfunction causes NMDA-receptor activation, which leads to further mitochondrial impairment. In this scenario, NMDA-receptor antagonists may be neuroprotective.

Abstract 1783: Pro-Apoptotic Bnip3 Mediates Permeabilization of Mitochondria and Release of Cytocrome c via a Novel Mechanism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Melissa N Quinsay ◽  
Shivaji Rikka ◽  
M Richard Sayen ◽  
Jeffery D Molkentin ◽  
Roberta A Gottlieb ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Heart Association ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Cyclophilin D ◽  
The Matrix

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. The pro-apoptotic Bcl-2 proteins mediate mitochondrial dysfunction independent of the mitochondrial permeability transition pore (mPTP). However, Bnip3 has been reported to mediate cell death via the mPTP. In this study, we investigated the mechanism(s) by which Bnip3 causes mitochondrial dysfunction. Using a mitochondrial swelling assay to assess pore opening, we found that addition of 200 microM Ca2+ to mitochondria isolated from rat hearts induced rapid swelling of mitochondria and release of cytochrome c (cyto c). Bnip3 also induced mitochondrial swelling and cyto c release, but always at a slower rate and to a greater degree, suggesting that Bnip3 mediates swelling via a different mechanism. Cyclosporin A (CsA), an inhibitor of mPTP opening, prevented Ca2+-induced swelling and cyto c release, but had no effect on Bnip3. Another BH3-only protein, tBid, caused release of cyto c but failed to induce swelling of mitochondria. Interestingly, Bnip3, but not Ca2+ and tBid, induced release of the matrix protein MnSOD. Cyclophilin D (cycD) is an essential component of the mPTP and heart mitochondria isolated from cycD−/− mice were resistant to Ca2+-, but not to Bnip3-induced swelling and cyto c release. Also, tBid caused cyto c release without mitochondrial swelling in the absence of cycD. To further explore the mPTP as a downstream effector of Bnip3-mediated cell death, we assessed cell death in mouse embryonic fibroblasts (MEFs) isolated from wild type (wt) and cycD−/− mice. Infection with an adenovirus expressing Bnip3 caused significant cell death in wt (52.8±1.8%) and cycD−/− (61.8±6.1%) MEFs as measured by LDH release. In addition, both Bnip3 and opening of the mPTP have been reported to initiate upregulation of autophagy. Monitoring of GFP-LC3 incorporation into autophagosomes by fluorescence microscopy revealed that Bnip3 infection induced autophagy in wt (86.5±6.6%) and cycD−/− (96.4±1.4%) MEFs (n=3, p<0.05). Thus, these studies suggest that Bnip3 mediates permeabilization of the inner and outer mitochondrial membranes via a novel mechanism that is different from other BH3-only proteins. This research has received full or partial funding support from the American Heart Association, AHA National Center.

scholarly journals Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Andrew C. Kent ◽  
Khairat Bahgat Youssef El Baradie ◽  
Mark W. Hamrick
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Low Grade ◽  
Mitochondrial Permeability ◽  
Mptp Opening

The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson’s disease (PD) and Alzheimer’s disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson’s disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.

scholarly journals Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak

2007 ◽  
Vol 405 (3) ◽  
pp. 407-415 ◽  
Author(s):  
Dieter A. Kubli ◽  
John E. Ycaza ◽  
Åsa B. Gustafsson
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Fluorescent Protein ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Dominant Negative ◽  
Dominant Negative Form ◽  
Wild Type Mefs ◽  
Green Fluorescent

Bnip3 is a pro-apoptotic member of the Bcl-2 family that is down-regulated in pancreatic cancers, which correlates with resistance to chemotherapy and a worsened prognosis. In contrast, Bnip3 is up-regulated in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion). Bnip3 exerts its action at the mitochondria, but the mechanism by which Bnip3 mediates mitochondrial dysfunction is not clear. In the present study, we have identified Bax and Bak as downstream effectors of Bnip3-mediated mitochondrial dysfunction. Bnip3 plays a role in hypoxia-mediated cell death, but MEFs (mouse embryonic fibroblasts) derived from mice deficient in Bax and Bak were completely resistant to hypoxia even with substantial up-regulation of Bnip3. These cells were also resistant to Bnip3 overexpression, but re-expression of Bax or Bak restored susceptibility to Bnip3, suggesting that Bnip3 can act via either Bax or Bak. In contrast, Bnip3 overexpression in wild-type MEFs induced mitochondrial dysfunction with loss of membrane potential and release of cytochrome c. Cell death by Bnip3 was reduced in the presence of mPTP (mitochondrial permeability transition pore) inhibitors, but did not prevent Bnip3-mediated activation of Bax or Bak. Moreover, overexpression of Bnip3ΔTM, a dominant-negative form of Bnip3, reduced translocation of GFP (green fluorescent protein)–Bax to mitochondria during sI/R (simulated I/R) in HL-1 myocytes. Similarly, down-regulation of Bnip3 using RNA interference decreased activation of Bax in response to sI/R in HL-1 myocytes. These results suggest that Bnip3 mediates mitochondrial dysfunction through activation of Bax or Bak which is independent of mPTP opening.

Curcumin Rescues a PINK1 Knock Down SH-SY5Y Cellular Model of Parkinson’s Disease from Mitochondrial Dysfunction and Cell Death

2016 ◽  
Vol 54 (4) ◽  
pp. 2752-2762 ◽  
Author(s):  
Celia van der Merwe ◽  
Hayley Christy van Dyk ◽  
Lize Engelbrecht ◽  
Francois Hendrikus van der Westhuizen ◽  
Craig Kinnear ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Cellular Model ◽  
Knock Down

scholarly journals Capsaicin Protects Cardiomyocytes against Anoxia/Reoxygenation Injury via Preventing Mitochondrial Dysfunction Mediated by SIRT1

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Huan He ◽  
Yue Zhou ◽  
Jiyi Huang ◽  
Zelong Wu ◽  
Zhangping Liao ◽  
...  
Keyword(s):  
Cell Viability ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Neonatal Rat ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Beneficial Effects ◽  
Sirt1 Inhibitor

Capsaicin (Cap) has been reported to have beneficial effects on cardiovascular system, but the mechanisms underlying these effects are still poorly understood. Apoptosis has been shown to be involved in mitochondrial dysfunction, and upregulating expression of SIRT1 can inhibit the apoptosis of cardiomyocytes induced by anoxia/reoxygenation (A/R). Therefore, the aim of this study was to test whether the protective effects of Cap against the injury to the cardiomyocytes are mediated by SIRT1. The effects of Cap with or without coadministration of sirtinol, a SIRT1 inhibitor, on changes induced by A/R in the cell viability, activities of lactate dehydrogenase (LDH), creatine phosphokinase (CPK), levels of intracellular reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), related protein expression, mitochondrial permeability transition pore (mPTP) opening, and apoptosis rate in the primary neonatal rat cardiomyocytes were tested. Cap significantly increased the cell viability, upregulated expression of SIRT1 and Bcl-2, and decreased the LDH and CPK release, generation of ROS, loss of MMP, mPTP openness, activities of caspase-3, release of the cytochrome c, and apoptosis of the cardiomyocytes. Sirtinol significantly blocked the cardioprotective effects of Cap. The results suggest that the protective effects of Cap against A/R-induced injury to the cardiomyocytes are involved with SIRT1.

scholarly journals BNIP3 and Genetic Control of Necrosis-Like Cell Death through the Mitochondrial Permeability Transition Pore

2000 ◽  
Vol 20 (15) ◽  
pp. 5454-5468 ◽  
Author(s):  
C. Vande Velde ◽  
J. Cizeau ◽  
D. Dubik ◽  
J. Alimonti ◽  
T. Brown ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Nuclear Translocation ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Outer Membrane ◽  
Plasma Membrane Permeability ◽  
Mitochondrial Permeability ◽  
Bh3 Domain

ABSTRACT Many apoptotic signaling pathways are directed to mitochondria, where they initiate the release of apoptogenic proteins and open the proposed mitochondrial permeability transition (PT) pore that ultimately results in the activation of the caspase proteases responsible for cell disassembly. BNIP3 (formerly NIP3) is a member of the Bcl-2 family that is expressed in mitochondria and induces apoptosis without a functional BH3 domain. We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. However, cells transfected with BNIP3 exhibit early plasma membrane permeability, mitochondrial damage, extensive cytoplasmic vacuolation, and mitochondrial autophagy, yielding a morphotype that is typical of necrosis. These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Δψm) suppression, and increased reactive oxygen species production. The PT pore inhibitors cyclosporin A and bongkrekic acid blocked mitochondrial dysregulation and cell death. We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction.

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