Targeting the Mitochondrial Permeability Transition Pore to Prevent Age‐Associated Cell Damage and Neurodegeneration

Kent, Andrew; Baradie, Khairat Bahgat Youssef El; Hamrick, Mark W.

doi:10.1155/2021/6626484

Cited by 58 publications

(28 citation statements)

References 143 publications

(127 reference statements)

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“…Alteration in mPT by chemotherapy might influence cell destiny by altering the physiological activity of mPTPC. As a result, it is suggested that forcing the mitochondrial permeability transition pore (mPTP) to open or close for an extended period of time is toxic to the cell [26,67]. For example, pretreatment of mPT with a pore inhibitor, Cyclosporin A (CsA), or a pore opener sensitizer, PK11195, has been discovered to increase mitochondrial apoptosis triggered by resveratrol, a natural polyphenol [68].…”

Section: Mitochondrial Permeability Transition Pore Complex (Mptpc)mentioning

confidence: 99%

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

Bahar

Han

Kim

et al. 2022

Cancers

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Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.

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Section: Mitochondrial Permeability Transition Pore Complex (Mptpc)mentioning

confidence: 99%

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

Bahar

Han

Kim

et al. 2022

Cancers

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“…mtCa 2+ overload is one of the major causes of mPTP opening ( Kwong, 2017 ). The opening of the mPTP can cause mitochondrial depolarization and ROS production ( Kent et al, 2021 ). In our observations, sorafenib and regorafenib increased mtCa 2+ overload, which was evidenced by the calcium indicator mito-pericam.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the PINK1-Parkin Pathway Enhances the Lethality of Sorafenib and Regorafenib in Hepatocellular Carcinoma

et al. 2022

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Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies and the main cause of cancer-related deaths. The multitarget tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib are systemic therapeutic drugs approved for the treatment of HCC. Here, we found that sorafenib and regorafenib injured mitochondria by inducing mitochondrial Ca2+ (mtCa2+) overload and mitochondrial permeability transition pore (mPTP) opening, resulting in mitochondria-mediated cell death, which was alleviated by cyclosporin A (CsA), an inhibitor of mPTP. Meanwhile, mPTP opening caused PINK1 accumulation on damaged mitochondria, which recruited Parkin to mitochondria to induce mitophagy. Inhibition of autophagy by the lysosomal inhibitor chloroquine (CQ) or inhibition of mitochondrial fission by mdivi-1 aggravated sorafenib- and regorafenib-induced cell death. Moreover, knockdown of PINK1 also promotes sorafenib- and regorafenib-induced cell death. An in vivo study showed that sorafenib and regorafenib inhibited HepG2 cell growth more effectively in PINK1 knockdown cells than in shNTC cells in null mice. Thus, our data demonstrate that PINK1-Parkin-mediated mitophagy alleviates sorafenib and regorafenib antitumor effects in vitro and in vivo.

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“…Mitochondrial ROS production and induction of apoptosis is closely related to many degenerative diseases, including neurodegeneration [ 55 , 56 , 57 ]. In the current study, we showed mitochondrial ERβ-dependent resistance in the induction of apoptosis upon treatment of the cells with either the apoptotic stimulus staurosporine or the oxidative stress stimulus H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Tsialtas

Georgantopoulos

Karipidou

et al. 2021

IJMS

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Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H2O2-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.

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Targeting the Mitochondrial Permeability Transition Pore to Prevent Age‐Associated Cell Damage and Neurodegeneration

Cited by 58 publications

References 143 publications

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

Inhibition of the PINK1-Parkin Pathway Enhances the Lethality of Sorafenib and Regorafenib in Hepatocellular Carcinoma

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

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