Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

Abstract

Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.

Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

“…A number of proof-of-concept studies have been performed with compounds targeting autophagy in vitro in cells and in vivo, generally in genetically-deficient animal models. The molecules tested were designed to target mitophagy, macroautophagy, CMA, or lysosomes ( Table 3 [ 196 ]). In the context of mitophagy, since oxidative stress is one of the principal causes of mitochondrial dysfunction, the agents assessed mainly protect against the production of, or neutralize, free radicals.…”

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

“…Subsequently, protein accumulation leads to widespread microglial activation and triggers the activation of inflammatory pathways and release of pro-inflammatory mediators, which, in turn, further increases ROS generation, OS, protein aggregation and neuronal damage. In this vicious cycle, degradation of misfolded proteins and damaged organelles by the ubiquitin/proteasome system and autophagy is also impaired [5,6,8,10,[26][27][28][29][30]. Regarding oxidative damage of lipid molecules, increased production of 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxidation, prevents removal of glutamate by inhibiting glutamate transporters, which together with the ATP depletion, promotes glutamate-mediated excitotoxicity and increases nitric oxide (NO) production.…”

“…Mitophagy is vital for sustaining redox homeostasis and neuronal survival under OS. However, when the levels of OS are high, mitophagy is decreased, which results in the accumulation of damaged mitochondria and massive cell death [8]. In OS conditions, mitophagy is regulated by the PINK1-Parkin axis.…”

“…Together with the unique fingerprint that is typical for each of these diseases (mostly related to distinct proteins that form deposits and the selective vulnerability of specific brain areas), they all have several underlying mechanisms in common. These include oxidative stress (OS), impairment of mitochondrial function, excitotoxicity, chronic inflammatory response and gliosis, protein misfolding, aggregation and accumulation, deregulation of autophagy and proteosomal protein degradation, alterations in the brain lipid profile and disturbed ceramide metabolism, impairment of synaptic function and, ultimately, neuronal death [2][3][4][5][6][7][8].…”

The Peroxisome-Autophagy Redox Connection: A Double-Edged Sword?

“…Currently, it is widely accepted that autophagy represents a prime mechanism of protection against oxidative damage ( Ornatowski et al, 2020 ; Yun et al, 2020 ). In addition, autophagic activity is governed by complex redox-mediated signaling pathways that, depending on the context, exert positive or negative regulatory activities at the transcriptional and/or protein level ( Scherz-Shouval et al, 2007a ; Park et al, 2021a ; Redza-Dutordoir and Averill-Bates, 2021 ; Zhou et al, 2021 ). In the following subsections, we first briefly explain the mechanisms behind H 2 O 2 signaling.…”