• 대한의생명과학회지
• /
• 제19권2호
• /
• pp.83-89
• /
• 2013

Parkin is a protein known to have tumor suppressive functions. In a previous study, we determined that Parkin expression restores susceptibility to TNF-${\alpha}$-induced death in HeLa cells. ${\beta}$-catenin is a key protein in the Wnt signaling pathway and excessive activation of the ${\beta}$-catenin pathway can promote cancer development. In this study, we found that ${\beta}$-catenin levels decreased dramatically in Parkin over-expressing HeLa cells treated with TNF-${\alpha}$. We used chemical inhibitors of cell signaling pathways to identify the signaling molecules involved in ${\beta}$-catenin down-regulation. Our results indicate that the PKC inhibitor (RO-31-7549) blocked parkin-induced down-regulation of ${\beta}$-catenin. We also show that Parkin-induced decrease in cell viability in TNF-${\alpha}$-treated HeLa cells is alleviated upon treatment with a PKC inhibitor. Taken together, these results suggest the possibility that ${\beta}$-catenin reduction may be associated with Parkin-induced decrease of cell viability in TNF-${\alpha}$ treated HeLa cells.

• 생명과학회지
• /
• 제32권10호
• /
• pp.771-777
• /
• 2022

파킨슨병에서의 도파민 신경세포의 사멸 원인은 다양하며 별개의 유전적 요소와 환경적 요소들이 관여한다. 드물게 발생하는 유전성 파킨슨병에서 parkin의 돌연변이와 기능 상실은 주로 소포체 스트레스를 통해 중뇌 흑질의 도파민 신경세포를 특이적으로 손상시킨다. 상대적으로 일반적인 특발성 파킨슨병에서는 살충제 노출이 역학적으로 중요하다. 그러나 환경독성물질에의 노출과 유전성 파킨슨병의 연관성에 대해서는 잘 알려진 바가 없다. 본 연구에서는 잘 확립된 중뇌 유래의 도파민 신경세포주인 N27-A를 사용하여 특발성 파킨슨병과 유전성 파킨슨병 사이의 공통된 발병 기작의 증거를 확인하였다. 특발성 파킨슨병을 유발하는 유기염소계 살충제인 디엘드린은 BiP/Grp78, 헴산화효소-1과 같은 소포체 스트레스 반응 표지자를 발현 유도하였고, 특히 parkin 단백질의 발현을 증가시켰다. 디엘드린이 N27-A 세포를 사멸시키는 과정에서 소포체 스트레스 특이적 세포사를 매개하는 Caspase-12의 활성화가 유의미하게 증가하였다. 흥미롭게도 디엘드린에 의한 N27-A 세포의 사멸이 소포체 단백질인 parkin과 Bcl-2의 과발현시 유의미하게 억제되었다. 본 연구 결과, 소포체 스트레스의 누적이 특발성, 유전성 파킨슨병의 공통의 발병 기작일 가능성이 있으며, 몇 가지 소포체 관련 단백질들이 디엘드린에 의한 도파민 신경세포 손상으로부터 보호 효과를 가지는 것으로 보인다.

• BMB Reports
• /
• 제55권7호
• /
• pp.354-359
• /
• 2022

MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-II protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria.

• Journal of Ginseng Research
• /
• 제47권3호
• /
• pp.448-457
• /
• 2023

Background: Alzheimer's disease (AD) is a common form of dementia, and impaired mitophagy is a hallmark of AD. Mitophagy is mitochondrial-specific autophagy. Ginsenosides from Ginseng involve in autophagy in cancer. Ginsenoside Rg1 (Rg1 hereafter), a single compound of Ginseng, has neuroprotective effects on AD. However, few studies have reported whether Rg1 can ameliorate AD pathology by regulating mitophagy. Methods: Human SH-SY5Y cell and a 5XFAD mouse model were used to investigate the effects of Rg1. Rg1 (1µM) was added to β-amyloid oligomer (AβO)-induced or APPswe-overexpressed cell models for 24 hours. 5XFAD mouse models were intraperitoneally injected with Rg1 (10 mg/kg/d) for 30 days. Expression levels of mitophagy-related markers were analyzed by western blot and immunofluorescent staining. Cognitive function was assessed by Morris water maze. Mitophagic events were observed using transmission electron microscopy, western blot, and immunofluorescent staining from mouse hippocampus. The activation of the PINK1/Parkin pathway was examined using an immunoprecipitation assay. Results: Rg1 could restore mitophagy and ameliorate memory deficits in the AD cellular and/or mouse model through the PINK1-Parkin pathway. Moreover, Rg1 might induce microglial phagocytosis to reduce β-amyloid (Aβ) deposits in the hippocampus of AD mice. Conclusion: Our studies demonstrate the neuroprotective mechanism of ginsenoside Rg1 in AD models. Rg1 induces PINK-Parkin mediated mitophagy and ameliorates memory deficits in 5XFAD mouse models.

• 한국자기학회:학술대회 개요집
• /
• 한국자기학회 2008년도 Asian Magnetics Conference
• /
• pp.259.1-259.1
• /
• 2008

• 한국동물학회:학술대회논문집
• /
• 한국동물학회 2003년도 한국생물과학협회 학술발표대회
• /
• pp.214.2-214
• /
• 2003

No Abstract, See Full Text

• Journal of Ginseng Research
• /
• 제46권1호
• /
• pp.138-146
• /
• 2022

Background: Red Ginseng has been used for many years to treat diseases. Ginsenoside Rg3 has documented therapeutic effects, including anticancer and anti-inflammatory activities. However, the anticancer effect of Rg3-enriched red ginseng extract (Rg3-RGE) and its underlying mechanisms have not been fully explored. We investigated whether Rg3-RGE plays an anti-tumor role in lung cancer cells. Methods: To examine the effect of Rg3-RGE on lung cancer cells, we performed cell viability assays, flow cytometry, western blotting analysis, and immunofluorescence to monitor specific markers. Results: Rg3-RGE significantly inhibited cell proliferation and induced mitochondria-dependent apoptosis. Furthermore, Rg3-RGE also increased expression of mitophagy-related proteins such as PINK1 and Parkin. In addition, treatment with Rg3-RGE and mitophagy inhibitors stimulated cell death by inducing mitochondria dysfunction. Conclusions: Rg3-RGE could be used as a therapeutic agent against lung cancer.

• 한국자기학회:학술대회 개요집
• /
• 한국자기학회 2011년도 임시총회 및 하계학술연구발표회
• /
• pp.56-56
• /
• 2011

• 한국자기학회:학술대회 개요집
• /
• 한국자기학회 2008년도 Asian Magnetics Conference
• /
• pp.200.2-200.2
• /
• 2008

• BMB Reports
• /
• 제54권12호
• /
• pp.592-600
• /
• 2021

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly population and is caused by the loss of dopaminergic neurons. PD has been predominantly attributed to mitochondrial dysfunction. The structural alteration of α-synuclein triggers toxic oligomer formation in the neurons, which greatly contributes to PD. In this article, we discuss the role of several familial PD-related proteins, such as α-synuclein, DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails a selective degradation of mitochondria via autophagy. Defective changes in mitochondrial dynamics and their biochemical and functional interaction induce the formation of toxic α-synuclein-containing protein aggregates in PD. In addition, these gene products play an essential role in ubiquitin proteasome system (UPS)-mediated proteolysis as well as mitophagy. Interestingly, a few deubiquitinating enzymes (DUBs) additionally modulate these two pathways negatively or positively. Based on these findings, we summarize the close relationship between several DUBs and the precise modulation of mitophagy. For example, the USP8, USP10, and USP15, among many DUBs are reported to specifically regulate the K48- or K63-linked de-ubiquitination reactions of several target proteins associated with the mitophagic process, in turn upregulating the mitophagy and protecting neuronal cells from α-synuclein-derived toxicity. In contrast, USP30 inhibits mitophagy by opposing parkin-mediated ubiquitination of target proteins. Furthermore, the association between these changes and PD pathogenesis will be discussed. Taken together, although the functional roles of several PD-related genes have yet to be fully understood, they are substantially associated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship provides valuable therapeutic clues for appropriate management strategies.