NYMC Faculty Publications

Dysfunctional Lysosomal Autophagy Leads to Peroxisomal Oxidative Burnout and Damage During Endotoxin-Induced Stress

Author Type(s)

Faculty

DOI

10.4161/auto.23344

Journal Title

Autophagy

First Page

442

Last Page

444

Document Type

Article

Publication Date

3-1-2013

Department

Medicine

Keywords

Acyl-CoA Oxidase, Adaptor Proteins, Signal Transducing, Animals, Autophagy, Catalase, Cell Proliferation, DNA Damage, Endotoxins, Heat-Shock Proteins, Hydrogen Peroxide, Lipopolysaccharides, Lysosomes, Mice, Mice, Transgenic, Oxidative Stress, Peroxisomes, Sequestosome-1 Protein

Disciplines

Medicine and Health Sciences

Abstract

Mammalian peroxisomes are ubiquitous organelles that possess a comprehensive ensemble of more than 50 enzymes. Cells regulate the number of organelles through dynamic interplay between biogenesis and degradation. Under basal conditions, approximately 30% of the peroxisomal pool is turned over daily. Recycling of peroxisomes is necessary for preservation of their functional competence, and correctly functioning autophagic/lysosomal pathways play a central role. In this study, we investigated (1) how lipopolysaccharide (LPS) influences peroxisomal dynamics and functions; and (2) how a superimposed lysosomal dysfunction affects pexophagy and modifies peroxisomal responses to LPS. We demonstrated that a transiently increased autophagic degradation of peroxisomes, pexophagy, followed by increased proliferation of peroxisomes is a default response to endotoxic stress. Impairment of autophagy due to lysosomal dysfunction, however, abolishes the above peroxisomal dynamics and results in accumulation of functionally compromised peroxisomes. These exhibit an imbalance between preserved hydrogen peroxide (H 2O 2)-generating acyl-CoA oxidase (ACOX) and dysfunctional/inactivated catalase (CAT), which leads to intra-peroxisomal redox disequilibrium. This metabolic-oxidative mismatch causes further worsening of peroxisomal functions, peroxisomal burnout, with the consequence of enhanced oxidative stress and aggravated organ injury.

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