Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus

Abstract

Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca 2+ , ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5 −/− mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca 2+ /calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5 −/− mice than WT mice. Furthermore, treatment with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5 −/− mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding ironmediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.

Iron Homeostasis Disorder and Alzheimer’s Disease

“…Even more evidence supports a key role of ROS and RNS (reactive nitrogen species) in leading to AD, which are toxic and related to the formation of oxidative stress in the brain of AD patients [104]. The oxidative stress was more obvious with the increase in iron concentration, and the oxidation of protein, lipid and DNA in Aβ aggregation area was more significant [105,106]. The free radicals produced at regions of Aβ aggregation will destroy the adjacent neurons, resulting in a decline in cognitive and memory functions.…”

“…Brain iron excess induces oxidative stress through Fenton chemical reactions, which cause damage to protein, lipid and DNA [7], and lead to ryanodine-receptor-mediated calcium release under the stress, resulting in neurotoxicity [105]. Small molecular substances have been designed for ROS scavenging at fixed sites.…”

Mitochondrial Redox Signaling Is Critical to the Normal Functioning of the Neuronal System

“…There are two subtypes of Prxs in mitochondria, Prx3 and Prx5. These Prxs are implicated in the development of various neurological disorders, as shown experimentally using transgenics and mutants (Chen et al, 2012(Chen et al, , 2014Davey and Bolanos, 2013;Angeles et al, 2014;Kim et al, 2016;Park et al, 2017;Agrawal and Fox, 2019;Pharaoh et al, 2019;Wang et al, 2019;Lee et al, 2020).…”

Nanomedicine targets iron metabolism for cancer therapy

“…Some evidence has shown the correlation of dysregulation of iron with the development of cancer in humans. Cancer cells reshape the pathways of iron metabolism to meet the high iron demand during tumor growth and malignancy 3 . The vigorous aerobic glycolysis process of tumor cells is closely related to iron metabolism.…”