Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death

Abstract

Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized. Antioxid. Redox Signal. 11,[481][482][483][484][485][486][487][488][489][490][491][492][493][494][495][496]

The Clavesin Family, Neuron-specific Lipid- and Clathrin-binding Sec14 Proteins Regulating Lysosomal Morphology

“…Moreover, it is interesting that clavesins function in trafficking to lysosomes. The importance of lysosomes for cell survival is underscored not only by their ability to degrade damaged macromolecules but also by the fact that compromised lysosomal function can lead to apoptotic cell death (55). Neurons are particularly sensitive to lysosomal dysfunction, and alterations in lysosomal function are the underlying cause of numerous neurodegenerative diseases (55).…”

“…The importance of lysosomes for cell survival is underscored not only by their ability to degrade damaged macromolecules but also by the fact that compromised lysosomal function can lead to apoptotic cell death (55). Neurons are particularly sensitive to lysosomal dysfunction, and alterations in lysosomal function are the underlying cause of numerous neurodegenerative diseases (55). These data imply that neurons have unique mechanisms for regulation 1-1, 1-2), two different miRNAs targeting clavesin 2 (2-1, 2-2), or different combinations of the clavesin 1 and 2 miRNAs, as indicated.…”

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

“…Given its role in clearing damaged organelles and macromolecules ( 17 ), it is plausible that autophagy is impacted by ROS in cardiac lipotoxicity. ROS overproduction was linked to impaired lysosomal function in certain neurological diseases and in cultured hepatocytes, which could impact autophagic turnover ( 18,19 ). Whether ROS modulates cardiac autophagy in response to lipid overload, as in obesity and diabetes, is unclear.…”

Effects of the combined administration of vitamins C and E on the oxidative stress status and programmed cell death pathways after experimental spinal cord injury

“…Recent evidence supports a protective role of the lysosomal compartment, as part of the oxidative stress response. 19 Protective effects of VCE against apoptotic cell death are well described in the literature: VCE diminishes homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. 8 Combined treatment with VCE reduced caspase-9 and -3 activities and myocyte apoptosis.…”