Browsing by Author "Arindam Ghosh"

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Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells
(Taylor and Francis Ltd., 2024) Upasana Ganguly; Sukhpal Singh; Aritri Bir; Arindam Ghosh; Sankha Shubhra Chakrabarti; Reena V. Saini; Luciano Saso; Marco Bisaglia; Sasanka Chakrabarti
Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Dimethyl-2-oxoglutarate but not antioxidants prevents glucose hypometabolism induced neural cell death: implications in the pathogenesis and therapy of Alzheimer's disease
(Elsevier B.V., 2025) Aman Chauhan; Karanpreet Bhutani; Aritri Bir; Ajay Singh; Sankha Shubhra Chakrabarti; Adesh K. Saini; Sasanka Chakrabarti; Arindam Ghosh
Cerebral glucose hypometabolism is a cardinal molecular signature of Alzheimer's disease, and its role in the pathogenesis of this disorder is under intensive study in both animal and cell-based models. In the current study, we exposed SH-SY5Y cells (human neuroblastoma cell line) over a period of 48 h to DRB18, an inhibitor of multiple glucose transporters, in different concentrations to develop a state of glucose hypometabolism. Under this metabolic insult, in SH-SY5Y cells a profound dose-dependent neural cell death, an increased production of reactive oxygen radicals, mitochondrial membrane depolarization and a depletion of cellular ATP content were noted; these effects were not prevented by lipid-soluble novel antioxidants such as ferrostatin-1 and liproxstatin-1 or by a general water-soluble antioxidant like N-acetylcysteine. However, dimethyl-2-oxoglutarate, the cell-permeable analogue of 2-oxoglutarate (α-ketoglutarate) which can serve as an alternative fuel during glucose hypometabolism partially prevented both mitochondrial impairments and neural cell death. Thus, dimethyl-2-oxoglutarate may be explored further as a potential neuroprotective compound for Alzheimer's disease, and its effect on amyloid beta metabolism and homeostasis should be examined under glucose hypometabolic stress. © 2025 The Authors