Cellular Uptake and Delivery of Myeloperoxidase to Lysosomes Promote Lipofuscin Degradation and Lysosomal Stress in Retinal Cells

Abstract

Neutrophil myeloperoxidase (MPO) catalyzes the HO-dependent oxidation of chloride anion to generate hypochlorous acid, a potent antimicrobial agent. Besides its well defined role in innate immunity, aberrant degranulation of neutrophils in several inflammatory diseases leads to redistribution of MPO to the extracellular space, where it can mediate tissue damage by promoting the oxidation of several additional substrates. Here, we demonstrate that mannose 6-phosphate receptor-mediated cellular uptake and delivery of MPO to lysosomes of retinal pigmented epithelial (RPE) cells acts to clear this harmful enzyme from the extracellular space, with lysosomal-delivered MPO exhibiting a half-life of 10 h. Lysosomal-targeted MPO exerts both cell-protective and cytotoxic functions. From a therapeutic standpoint, MPO catalyzes the degradation of-retinylidene--retinylethanolamine, a toxic form of retinal lipofuscin that accumulates in RPE lysosomes and drives the pathogenesis of Stargardt macular degeneration. Furthermore, chronic cellular uptake and accumulation of MPO in lysosomes coincides with -retinylidene--retinylethanolamine elimination in a cell-based model of macular degeneration. However, lysosomal-delivered MPO also disrupts lysosomal acidification in RPE cells, which coincides with nuclear translocation of the lysosomal stress-sensing transcription factor EB and, eventually, cell death. Based on these findings we predict that under periods of acute exposure, cellular uptake and lysosomal degradation of MPO mediates elimination of this harmful enzyme, whereas chronic exposure results in progressive accumulation of MPO in lysosomes. Lysosomal-accumulated MPO can be both cell-protective, by promoting the degradation of toxic retinal lipofuscin deposits, and cytotoxic, by triggering lysosomal stress and cell death.

Oxidative stress in chronic kidney disease

“…Myeloperoxidase MPO, a heme-containing peroxidase that is synthesized during myeloid differentiation, is abundantly stored in azurophilic granules of leukocytes. Normally, MPO catalyzes the formation of HClO from the H 2 O 2 -mediated oxidation of halide ions [24]. However, in various diseases, degranulation leads to the release of MPO into the extracellular space, where it can oxidize not only halide ions but also other substrates to mediate tissue damage [25].…”

Altered activation state of circulating neutrophils in patients with neovascular age-related macular degeneration

“…In Parkinson’s disease and Alzheimer’s disease, MPO is redistributed into the extracellular space where it mediates tissue damage [ 16 , 17 ], which is a mechanism suspected of contributing to the pathogenesis of AMD. Accumulated MPO is a two-edged sword: it may be beneficial by clearing toxic retinal lipofuscin deposits, but may be harmful by causing lysosomal stress that results in cell death [ 18 ].…”

Oral Health Status of Patients with Lysosomal Storage Diseases in Poland

“…Thus, increased levels of MPO in saliva may be viewed as a protective response to insults to oral homeostasis [32]. Indeed, increased MPO has been shown to promote the degradation of toxic lysosomal deposits [33]. On the other hand, however, a chronically increased MPO activity may lead to lysosomal stress and cell death [33].…”

“…Indeed, increased MPO has been shown to promote the degradation of toxic lysosomal deposits [33]. On the other hand, however, a chronically increased MPO activity may lead to lysosomal stress and cell death [33]. …”