Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases. We ascribe this to the emerging literature which suggests that the oxidative stress hypothesis does not encompass the role of reactive species in cell signaling and therefore the interception with reactive species with antioxidant supplementation may result in disruption of redox signaling. In addition, the accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. We have proposed that autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival. In this review, we will highlight observations regarding the impact of autophagy regulation on cellular bioenergetics and survival in response to reactive species or reactive species generating compounds, and in response to proteotoxic stress.
Redmann Matthew,Darley-Usmar Victor,Zhang Jianhua. The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases[J]. Aging and disease,
2016, 7(2): 150-162.
Figure 1. Autophagy serves as an essential neuroprotective pathway in response to mitochondrial dysfunction and oxidative stress. In neurodegenerative diseases, AD, PD, and stroke, mitochondrial dysfunction accumulates due to aging, genetic abnormalities, environmental damage (such as pesticides), or neuroinflammation (which induces excessive production of nitric oxide, among others), resulting in decreased oxidative phosphorylation, and accumulation of mtDNA damage. There are also increases in protein damage, including protein oxidation and formation of HNE-protein adducts. Whether absolute levels of ROS are directly correlated with aging process is debatable. Emerging evidence indicated that transient or moderate ROS elevation may trigger response in ER stress and mitochondrial unfolded protein response pathways, as well as adaptations mediated by HIF, NRF2 and other transcription factor-regulated mechanisms (such as Apaf1 and Caspase-9 dependent mitochondria to nuclear signaling). Therefore, a systemic decrease of ROS is unlikely to be the best approach to delay aging and age related neurodegeneration. Clearance of damaged proteins and organelles are dependent on the autophagy process, which involve double membrane vesicles encircling these damaged intracellular materials and sending them to be degraded. It has been hypothesized that dysfunction of autophagy promotes neurodegeneration and enhancement of autophagy may be neuroprotective.
Figure 2. Autophagy may be used to attenuate α-synuclein secretion and inter-cellular propagation. α-synuclein fibrils (PFF) (red circles) recruit endogenous α-synuclein (aSyn) (yellow circles) to form aggregates and induce neuron death. Aggregates can also be released and propagate to neighboring cells and further pathological damage to the brain. Enhanced lysosomal efficiency/hydrolytic capacity through increased Cathepsin D or enhanced autophagosome production through trehalose treatment may promote the sequestering and degradation of toxic α-synuclein species.
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