Search

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics., (Copyright © 2022. Published by Elsevier B.V.)

A failure in redox homeostasis is a common hallmark of Alzheimer's Disease (AD) and Parkinson's Disease (PD), two age-dependent neurodegenerative disorders (NDD), causing increased oxidative stress, oxidized/damaged biomolecules, altered neuronal function and consequent cell death. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-regulated transcription factor, results in upregulation of cytoprotective and antioxidant enzymes/proteins, protecting against oxidative stress. Nrf2 regulation is achieved by various proteins and pathways, at both cytoplasmatic and nuclear level; however, the elaborate network of mechanisms involved in Nrf2 regulation may restrain Nrf2 pathway normal activity. Indeed, altered Nrf2 activity is involved in aging and NDD, such as AD and PD. Therefore, understanding the diversity of Nrf2 control mechanisms and regulatory proteins is of high interest, since more effective NDD therapeutics can be identified. In this review, we first introduce Keap1-Nrf2-ARE structure, function and regulation, with a special focus on the several pathways involved in Nrf2 positive and negative modulation, namely p62, PKC, PI3K/Akt/GSK-3β, NF-kB and p38 MAPK. We then briefly describe the evidences for oxidative stress and Nrf2 pathway deregulation in different stages of NDDs. Finally, we discuss the potential of Nrf2-related pathways as potential therapeutic targets to possibly prevent or slowdown NDD progression., (Copyright © 2019 Elsevier B.V. All rights reserved.)