Biphasic regulation of lysosomal exocytosis by oxidative stress.
Oxidative stress drives cell death in a number of diseases including ischemic stroke and neurodegenerative diseases. A better understanding of how cells recover from oxidative stress is likely to lead to better treatments for stroke and other diseases. The recent evidence obtained in several models ties the process of lysosomal exocytosis to the clearance of protein aggregates and toxic metals. The mechanisms that regulate lysosomal exocytosis, under normal or pathological conditions, are only beginning to emerge. Here we provide evidence for the biphasic effect of oxidative stress on lysosomal exocytosis. Lysosomal exocytosis was measured using the extracellular levels of the lysosomal enzyme beta-hexosaminidase (ß-hex). Low levels or oxidative stress stimulated lysosomal exocytosis, but inhibited it at high levels. Deletion of the lysosomal ion channel TRPML1 eliminated the stimulatory effect of low levels of oxidative stress. The inhibitory effects of oxidative stress appear to target the component of lysosomal exocytosis that is driven by extracellular Ca2+. We propose that while moderate oxidative stress promotes cellular repair by stimulating lysosomal exocytosis, at high levels oxidative stress has a dual pathological effect: it directly causes cell damage and impairs damage repair by inhibiting lysosomal exocytosis. Harnessing these adaptive mechanisms may point to pharmacological interventions for diseases involving oxidative proteotoxicity or metal toxicity.
Department of Biological Sciences, Pittsburgh, PA 15260, USA.
Sreeram
S
Ravi
Department of Biological Sciences, Pittsburgh, PA 15260, USA.
Karina A
KA
Peña
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Charleen T
CT
Chu
Department of Biological Sciences, Pittsburgh, PA 15260, USA. Electronic address: kiselyov@pitt.edu.
Kirill
K
Kiselyov
D002118:Calcium / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D019216:Metals, Heavy / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000378:metabolism; D014407:Tumor Cells, Cultured
C416674:MCOLN1 protein, human; D019216:Metals, Heavy; D050051:Transient Receptor Potential Channels; D002118:Calcium
Calcium; Exocytosis; Lysosomes; Oxidative stress; TRPML1