Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis.

Toxicology and Applied Pharmacology
Masayuki FukuiBao Ting Zhu

Abstract

Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K(3)) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ~12h) of mitochondrial superoxide-induced neuronal death. While ...Continue Reading

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Citations

Mar 19, 2013·Folia Microbiologica·Miroslav Pohanka
Nov 23, 2017·Photochemistry and Photobiology·Michael R Hamblin
Oct 16, 2016·Oncotarget·Hesti Lina WiraswatiNazanine Modjtahedi
Mar 6, 2019·Scientific Reports·Uma KizhuveetilG K Suraishkumar
Jan 27, 2015·Molecular Neurobiology·Bin CaiShao-Hua Yang
Nov 19, 2020·Oxidative Medicine and Cellular Longevity·Rumiana BakalovaTatsuya Higashi
May 5, 2021·Chemico-biological Interactions·Melania Iara FunkRomina María Uranga

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