Anavex Life Sciences Corp (AVXL)

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Autophagy promotes ferroptosis by degradation of ferritin
Wen Hou,Yangchun Xie,Xinxin Song,Xiaofang Sun,Michael T. Lotze,Herbert J. Zeh III,

ABSTRACT
Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death.

Link to full paper:
https://www.tandfonline.com/doi/pdf/10.1080/15548627.2016.1187366?needAccess=true

Phospholipid oxidation products in ferroptotic myocardial cell death
Aleksandra Stamenkovic, Grant N. Pierce, and Amir Ravandi
30 JUN 2019https://doi.org/10.1152/ajpheart.00076.2019

Cell death is an important component of the pathophysiology of any disease. Myocardial disease is no exception. Understanding how and why cells die, particularly in the heart where cardiomyocyte regeneration is limited at best, becomes a critical area of study. Ferroptosis is a recently described form of nonapoptotic cell death. It is an iron-mediated form of cell death that occurs because of accumulation of lipid peroxidation products. Reactive oxygen species and iron-mediated phospholipid peroxidation is a hallmark of ferroptosis. To date, ferroptosis has been shown to be involved in cell death associated with Alzheimer’s disease, Huntington’s disease, cancer, Parkinson’s disease, and kidney degradation. Myocardial reperfusion injury is characterized by iron deposition as well as reactive oxygen species production. These conditions, therefore, favor the induction of ferroptosis. Currently there is no available treatment for reperfusion injury, which accounts for up to 50% of the final infarct size. This review will summarize the evidence that ferroptosis can induce cardiomyocyte death following reperfusion injury and the potential for this knowledge to open new therapeutic approaches for myocardial ischemia-reperfusion injury.

https://physiology.org/doi/abs/10.1152/ajpheart.00076.2019?journalCode=ajpheart

Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease
Shashank Masaldan, Abdel Ali Belaidi, Scott Ayton, and Ashley I. Bush*
Author information Article notes Copyright and License information

Abstract
Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

Keywords: Alzheimer’s disease, iron homeostasis, ferroptosis, senescence, chelators

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630536/

Oxidative Stress and the Microbiota-Gut-Brain Axis
Laura Dumitrescu, 1 , 2 Iulia Popescu-Olaru, 1 , 2 Liviu Cozma, 1 , 2 Delia Tulba, 1 , 2 Mihail Eugen Hinescu, 3 , 4 Laura Cristina Ceafalan, 3 , 4 Mihaela Gherghiceanu, 3 , 4 and Bogdan Ovidiu Popescucorresponding author 1 , 2 , 4
Author information Article notes Copyright and License information

The gut-brain axis is increasingly recognized as an important pathway of communication and of physiological regulation, and gut microbiota seems to play a significant role in this mutual relationship. Oxidative stress is one of the most important pathogenic mechanisms for both neurodegenerative diseases, such as Alzheimer's or Parkinson's, and acute conditions, such as stroke or traumatic brain injury. A peculiar microbiota type might increase brain inflammation and reactive oxygen species levels and might favor abnormal aggregation of proteins. Reversely, brain lesions of various etiologies result in alteration of gut properties and microbiota. These recent hypotheses could open a door for new therapeutic approaches in various neurological diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304899/


Learn more about Fenton Reaction
https://www.sciencedirect.com/topics/immunology-and-microbiology/fenton-reaction